Background It is estimated that around 5% of people with asthma have severe asthma. Severe asthma typically presents with poor symptom control, impaired lung function and asthma exacerbations, despite regular inhaled steroids and additional controller medications. In the BEyond Allergic Th2-Severe Asthma clinical trials programme, we worked with severe asthma specialist centres in the United Kingdom to identify patients who experienced frequent asthma attacks (two or more per year), who were potentially eligible for stratified asthma treatments. Objectives There are currently two recognised subtypes of severe asthma which can be characterised by their level of eosinophils (a type of white blood cells). In the BEyond Allergic Th2-Severe Asthma clinical trial programme, we aimed to test whether a simple, once-daily oral antibiotic (doxycycline) can reduce asthma attacks in individuals with lower levels of eosinophils in peripheral blood (T2-Low arm: < 300 cells/µl). We also aimed to test whether a simple twice-daily oral drug (dexpramipexole) can reduce asthma attacks in individuals with high levels of eosinophils in peripheral blood (T2-High arm : ≥ 300 cells/µl). The trial was established using a master protocol and platform trial design with study protocols for the T2-High and T2-Low cohorts. Study outcomes The trial platform was successfully set up during the COVID-19 pandemic and opened across 13 sites in the United Kingdom for recruitment between August 2021 and September 2022, following a 12-month trial pause due to the pandemic. Several changes to the trial protocol were made to make the protocol easier to deliver due to pandemic restrictions. Due to capacity issues at National Health Service trusts in the United Kingdom following the pandemic, the trial was delayed in opening sites by approximately 4 months. Shortly after all sites were opened, a decision was made with the Trial Steering Committee and funders to close the dexpramipexole (T2-High) arm of the trial (October 2022), as the drug had moved on to definitive and confirmatory phase III trials. Recruitment into the doxycycline trial progressed slowly, largely in part due to challenges in finding people with asthma who had the required number of asthma attacks to be eligible, as attack rates in the United Kingdom fell during the pandemic. Furthermore, the trial was recruiting exclusively from severe asthma centres in the United Kingdom and did not have the funding required to change the recruitment model to include screening within primary care also. As a result of these factors, a decision was made by the sponsor of the trial to close the trial (April 2023), in line with National Institute for Health and Care Research post pandemic reset policy. Limitations and future work While no scientific conclusions can be drawn from this trial, following the pandemic a formal review of commercial clinical trials was commissioned by the government (Lord O’Shaughnessy review), with several recommendations to enhance clinical trial delivery in the United Kingdom. Many of the recommendations are applicable to non-commercial asthma trials. Furthermore, pivotal phase III trials of dexpramipexole are currently well underway. We would advocate the development of a Respiratory Clinical Trials Accelerator Platform for airways disease trials in the United Kingdom to support academic trials. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number 16/71/05. Plain language summary What did we want to improve? It is estimated that around 5% of people with asthma have severe asthma. This typically presents as a high number of symptoms and poor lung function, despite regular medications, and repeated asthma attacks frequently, requiring time off work and hospital admission. What did we do? We aimed to test whether a simple, once-daily oral antibiotic (doxycycline) can reduce asthma attacks in individuals with low levels of eosinophils. We also tested whether a simple, twice-daily oral drug (dexpramipexole) can reduce asthma attacks in individuals with high levels of eosinophils. Overall, we aimed to identify the right patients based upon a blood test, looking at a specific immune cell type (blood eosinophils), to give the right drugs with severe asthma. What did we find? Due to the COVID-19 pandemic, we had to pause the trial setup, and once we restarted the trial, there were major challenges in recruiting people with asthma to the trial. The recruitment challenges were mainly due to the impact of the pandemic on being able to find people with asthma that had the required number of documented asthma attacks in the year before entering the trial. One of the treatments, dexpramipexole, moved on to definitive global trials early in the trial course, which meant that we did not need to test it further. For these reasons, the trials group, in consultation with the sponsor and funder, decided to close the trial early. All patients enrolled into the trial were notified of trial closure and the reasons for this. What does this mean? Due to the small number of patients included and incomplete follow-up, no definitive conclusions could be made from this trial. However, dexpramipexole is currently being evaluated in definitive global clinical trials.

BACKGROUND:Biologic therapies are approved for uncontrolled severe asthma despite good adherence to inhaled corticosteroids (ICS) and additional controllers. We examined the adherence assessments used across UK Severe Asthma Centres (SACs) and their relationship with biologic continuation and response. METHODS:UK SACs completed a quantitative survey on adherence assessment practices in 2022. We included all adult patients with severe asthma patients on ICS starting biologic therapy from the UK Severe Asthma Registry, which collects pre-biologic adherence data, including medication possession ratio (MPR), fractional exhaled nitric oxide (FeNO) suppression testing and serum prednisolone levels. Biologic continuation and response were defined as continuation on any biologic and the same biologic after 1 year, respectively. Associations were determined using multivariable logistic regression. RESULTS:At 21 SACs, MPR for ICS was assessed at 19 (90%) centres, prednisolone and/or cortisol levels in patients on daily oral corticosteroids at 15 (71%), and FeNO suppression testing at 9 (43%). Of 3307 biologic-initiated patients, 1943 (59%) had MPR for ICS recorded, of which 1802 (93%) demonstrated good adherence (≥75% MPR). Only 110 (9%) and 272 (16%) had FeNO suppression and serum prednisolone results, respectively. Good ICS adherence was associated with 2.65-fold higher odds (95% CI 1.02 to 6.91) of biologic continuation, but not with biologic response (OR 1.37, 95% CI 0.50 to 3.76). CONCLUSION:Good pre-biologic ICS adherence, measured using MPR, is associated with biologic continuation at 1 year. Further research is needed to determine whether baseline adherence predicts biologic response based on clinical and biologic criteria.

BACKGROUND:The aim of biologic therapies in severe asthma is inhibition of type 2 (T2) inflammatory pathways. OBJECTIVE:We hypothesized that patients who achieve complete suppression of IL-5 and IL-4/IL-13 pathways with biologic therapy (FeNO <20 ppb and blood eosinophil count <0.15 × 109, considered biological remission) would have better outcomes than patients with incomplete suppression of T2 biology. METHODS:This was a retrospective analysis of patients with severe asthma in the United Kingdom Severe Asthma Registry who met strict national access criteria for biologics. Characteristics before the biologic and at annual review were compared across biologic remission (BR) and non-BR. RESULTS:Of 778 patients, 148 (19%) had BR and 630 (81%) non-BR. Biologic remission did not confer additional benefit in exacerbation reduction, oral steroid exposure, lung function improvement, symptom improvement, or T2 biomarker reduction. The BR cohort was less T2 high before commencing biologics. Long disease duration (adjusted odds ratio [adjOR] = 1.96; 95% CI, 1.17-3.28), macrolide therapy (adjOR = 2.08; 95% CI, 1.17-3.71), and smoking history (adjOR = 1.63; 95% CI, 1.11-2.39) were positive predictors of BR, whereas higher T2 biomarkers predicted non-BR. However, blood eosinophil count and FeNO both had a negative correlation with lung function. CONCLUSION:Patients who achieve BR do not have superior outcomes compared with those who do not achieve BR. Biologic remission denotes a cohort of patients with a lower burden of T2 disease and additional factors driving disease severity. However, suppression of T2 biology is important for lung function gain. Prospective evaluation of treatment strategies that completely suppress IL-5 and IL-4/IL-13 pathways in T2 composite-high patients is needed.

ABSTRACT Background Asthma is a heterogeneous disease characterized by overlapping clinical and inflammatory features. Objective This study aimed to provide insight into the systemic inflammatory profile in asthma, greater understanding of asthma endotypes and the contribution of genetic risk factors to both. Methods 4205 patients with asthma aged 16–60 were recruited from UK centers; serum cytokines were quantified from 708, including cytokines associated with Type 1, 2 and 17 inflammation. 3037 patients were genotyped for 25 single nucleotide polymorphisms associated with moderate‐severe asthma. Results Serum cytokines associated with Th2 inflammation showed high coordinated expression for example, IL‐4/IL‐5 (R2 = 0.513). The upper quartile of the serum cytokine data identified 43.7% of patients had high levels for multiple Th2 cytokines. However, the groups defined by serum cytokine profile were not clinically different. Childhood‐onset asthma was characterized by elevated total IgE, allergic rhinitis and dermatitis. Exacerbation prone patients had a higher BMI, smoking pack‐years, asthma control questionnaire score and reduced lung function. Patients with blood eosinophils of > 300 cells/µL had elevated total IgE and lower smoking pack‐years. None of these groups had a differential serum cytokine profile. Asthma risk alleles for; rs61816764 (FLG) and rs9303277 (IKFZ3) were associated with childhood onset disease (p = 2.67 × 10−4 and 2.20 × 10−7; retrospectively). No genetic variant was associated with cytokine levels. Conclusion Systemic inflammation in asthma is complex. Patients had multiple overlapping inflammatory profiles suggesting several disease mechanisms. Genetic risk factors for moderate‐severe asthma confirmed previous associations with childhood onset of asthma.

Background:∼5-10% of patients with asthma have severe disease. A proportion remain symptomatic despite suppression of T2-related inflammation but what drives persistent symptoms remains unclear. Eicosanoids exert a functional role in pulmonary inflammation. We explored the relationship between urinary eicosanoids, asthma symptoms, obesity and T2-biomarker status. Methods:Urine was sampled during a randomised controlled trial assessing corticosteroid optimisation using T2-biomarker directed care at scheduled study visits (n=728) and at exacerbation (n=103). Urine eicosanoid concentrations were measured by mass spectrometry, then log2-transformed, z-scored and concatenated by biosynthetic pathway generating six pathway scores. Results were stratified by T2 status (T2-low: exhaled nitric oxide fraction (F ENO) <20 ppb and blood eosinophil count (BEC) <0.15×109 cells·L-1; versus T2-high: F ENO ≥20 ppb and BEC ≥0.15×109 cells·L-1), symptoms (symptom-low: Asthma Control Questionnaire-7 (ACQ-7) <1.5; versus symptom-high: ACQ-7 ≥1.5) and obesity. Results:Isoprostane (pathway score p=0.02) and thromboxane (pathway score p=0.04) levels were higher in symptom-high versus symptom-low, T2-low participants. Isoprostane levels were greater in symptom-high versus symptom-low participants, irrespective of T2 status (pathway score p=0.01). Cysteinyl-leukotriene E4 levels (LTE4) were elevated in T2-high versus T2-low participants (pathway score p=0.0007), irrespective of symptoms. Corticosteroid exposure, obesity and exacerbations were not associated with increased eicosanoid levels (p≥0.05). Conclusion:Raised urinary eicosanoid levels of isoprostanes and thromboxanes were associated with increased symptoms in T2-low severe asthma. Elevated excretion of these metabolites in T2-low participants could reflect increased thromboxane-receptor (TP) activation, which may be promoting increased asthma severity and bronchoconstriction. Further research and interventions are needed to explore the role of TP modulation in T2-low severe asthma.

BACKGROUND:Confirmation of optimal inhaled corticosteroid use is essential before initiating biologic therapy. Fractional exhaled nitric oxide (FeNO) suppression testing (FeNOSuppT) is a proven phenotyping technique; however, its long-term effect on clinical outcomes remains unclear. OBJECTIVES:To assess the real-world feasibility of delivering FeNOSuppT alongside digital inhaler monitoring and to examine its effect on biologic initiation and clinical outcomes. METHODS:Prospective cohort study within 7 U.K. severe asthma centers. Patients received a sensor-enabled inhaled corticosteroid/long-acting β-agonist (ICS/LABA) inhaler during an initial appointment between July 2020 and June 2022. A positive FeNOSuppT was defined as greater than 42% FeNO reduction at short-term follow-up (typically 1-3 mo postbaseline). Biologic initiation and clinical outcomes were compared at short-term and long-term (typically 12 mo postbaseline) follow-up. RESULTS:Of 353 included patients, 257 (72.8%) completed the FeNOSuppT and 140 (54.5%) were positive. A positive FeNOSuppT was associated with greater improvements in the % predicted short-term forced expiratory volume in 1 second (FEV1%; 8.6% vs -0.3; P < .001) and the 6-Item Asthma Control Questionnaire (ACQ6; 0.7 vs 0.3; P = .001) compared with a negative test. Of 168 patients eligible for biologics who completed the FeNOSuppT, those with a positive result initiated biologics less often (48.2% vs 65.2%; P = .035). Despite this, there was a greater improvement in FEV1 (11.0% vs 2.3%; P = .016), and a similar reduction in both asthma symptoms (ACQ6 0.7 vs 0.8; P = .623) and exacerbations (66.7% vs 66.7%; P = .349) at long-term follow-up when compared with those with a negative FeNOSuppT. CONCLUSIONS:Delivering FeNOSuppT aligned with digital monitoring is feasible within routine care. A positive FeNOSuppT was associated with lower rates of biologic initiation, with similar clinical outcomes.

BACKGROUND:Obesity is a common comorbidity associated with poor outcomes in severe asthma. OBJECTIVE:We aimed to determine whether obesity is associated with an altered response to severe asthma biologic agents. METHODS:We analyzed data from the UK Severe Asthma Registry, a large UK-wide cohort of patients attending regional severe asthma services. We analyzed the change in clinical outcomes between baseline and first annual review visit by body mass index (BMI) category (healthy range [18.50-24.99], overweight [25.00-29.99], obese [30.00-39.99], and severely obese [≥40]) and biologic treatment status. RESULTS:The study cohort comprised 1956 patients, of whom 1477 (75.5%) commenced a biologic agent during the follow-up. Baseline Asthma Control Questionnaire-6 (ACQ-6) scores and rates of exacerbations, emergency department attendances, and hospital admissions were higher with increasing BMI category. Biologic treatment was associated with significant additional improvement in ACQ-6, compared with patients not receiving biologics, in overweight, obese, and severely obese patients. However, the ACQ-6 score after biologic treatment remained significantly different across BMI categories, with the mean score being 1.3 in the healthy weight group and 2.8 in the severely obese group (P < .001). Biologic treatment was associated with significant additional reductions in exacerbation rates in all BMI groups except for the severely obese group. CONCLUSIONS:Asthma biologic agents appear to have important clinical benefits across the spectrum of BMI. However, because patients with obesity start at a worse baseline with respect to symptoms and exacerbations, they are still more likely to remain uncontrolled after treatment.

Background: Severe asthma pathology encompasses a wide range of pulmonary and extrapulmonary treatable traits with a high prevalence of comorbidities. Although asthma-specific health-related quality-of-life measures are most sensitive to changes in asthma control, generic measures, such as EQ-5D-5L (EuroQol 5-Dimension 5-Level questionnaire), are potentially better for capturing the impact of comorbidities. Objective: We sought to examine the impact of pulmonary and extrapulmonary treatable traits on quality of life at initial severe asthma assessment, and to compare the characteristics of those patients whose quality of life does and does not improve during follow-up at severe asthma centers. Methods: Patients’ characteristics at baseline assessment within the UK Severe Asthma Registry were compared by EQ-5D-5L utility index quartile. Patients with follow-up review data were stratified by change in EQ-5D-5L utility index from baseline to follow-up, and characteristics similarly examined. Results: Patients in the quartiles with worst dysutility at baseline were observed to exhibit more treatable traits and in particular extrapulmonary traits associated with cumulative systemic corticosteroids, including obesity, anxiety/depression, and osteoporosis. In those patients whose quality of life improved over follow-up, a reduction in exacerbations, uncontrolled symptoms, and requirement for maintenance oral corticosteroids were observed. Conclusions: Both pulmonary and extrapulmonary treatable traits are important determinants of quality of life in severe asthma. Comorbidities associated with cumulative systemic corticosteroid exposure are particularly associated with worse quality of life, emphasizing the importance of early identification and management of severe asthma before comorbidities develop.

The Global Burden of Disease (GBD) study reported an estimated 269 million patients with asthma worldwide, including approximately 35 million in India.1, 2 Whilst prevalence of asthma and other allergic conditions such as eczema is relatively low, the substantial population burden is exacerbated by patchy health service frameworks, lower health literacy levels in rural areas, and high levels of indoor and outdoor air pollution. These make management of asthma challenging in India (Krishna, Krishna, Krishna, Lancet planet health).3-7 Previous studies exploring reasons for uncontrolled asthma in India have focussed mainly on the paediatric age group,8, 9 and data on adult asthma patients are sparse. This study aimed to understand patient and primary care physician views and perspectives regarding asthma, and the facilitators and barriers to uptake of treatment and engagement with health services in Vellore district, South India. Semi-structured interviews were conducted with a purposively selected sample of patients and primary care physicians to address the research aims. Patient interviewees (n = 46) were ≥18 years old and had physician-diagnosed asthma as per GINA 2021 guidelines.9 Patients were identified from three primary care sites selected to include rural, semi-urban and urban areas, drawing on the knowledge and networks of the India-based members of the research team. We contacted the Vellore branch of the Indian Medical Association and obtained a list of medical practitioners in Vellore. Physicians (n = 20) who manage asthma were shortlisted, including in rural, semi-urban and urban areas. Semi-structured interviews took place face to face and were conducted by the author team using topic guides designed to cover the primary research aims (Table 1). GERD, Hypertension GERD, Depression, anxiety, rheumatism, diaphram palsy, endometriosis Insomnia, hypertension, diabetes Further study details can be found at https://zenodo.org/records/10469856. Three main themes were identified from the data: patient understanding of treatment, barriers to access and improving asthma management. Physicians expressed concern over levels of patient adherence with prescribed care, citing poor knowledge and patients often being unable to provide an accurate symptom history. In apparent support of these claims, patient interviewees voiced fears that asthma is 'contagious', and expectations of a 'cure' for the condition. Some attributed onset to unlikely causes such as faulty medication, or poisonous water. Many self-described as adhering to prescribed treatment regimens, including tablets, inhalers or a combination of both. However, some expressed a reluctance to use inhalers for fear of becoming 'dependent'. Some physicians also described poor compliance following initial symptom relief. As a result of these limitations, some judged patients—especially those in older age categories—to be unable to appropriately use the Metered Dose Inhaler (MDI), and they therefore prescribed oral medication. This problem was compounded by the lack of time available to them to overcome the technical challenges patients faced, or to explain the benefits of inhalers. Patients reported obstacles to accessing mainstream health services, with financial barriers the most frequently cited. Some described reliance on family members to pay for treatment and others selling land and possessions for this reason. Linked to this were concerns about travel and waiting times, which were especially cited by patients in rural or semi-urban areas. Social stigma was also noted by physicians and a small but significant number of patients, who described people 'looking at them differently' or avoiding them due to their asthma. Many patients expressed a preference for alternative treatments (e.g., Ayurveda and Siddha medicine), or a willingness to supplement standard treatments with ointments, herbs and steam inhalation. Physicians reported shortages in training and education in asthma management since qualifying, and agreed that updated training would be beneficial, including in treatment of allergic rhinitis. Key points of consensus were that training should be practically focussed, available online (as well as in person) and should focus on 'refreshing' of core elements and updating on new developments. Other suggestions included targeted education and awareness raising for patients, allied with resources for follow-up, including via telephone. Training for patients and communities was recommended in areas of prevention/lifestyle, management and combatting social stigma. Patients and physicians emphasized the need to address affordability of treatment, for example, through reducing treatment costs for lower socio-economic patient populations and offering online consultations. Cultural and religious aspects were important in shaping attitudes and behaviours, and this was consistent across geographical groups. Purposive sampling of participants from varying settings within the Vellore district make our findings widely relevant with respect to geographical area of residence, given the differences in socio-economic status, literacy, levels of indoor and outdoor pollution, access to medical care, and cultural and social factors. The study sample is also diverse with respect to age, gender and socio-economic strata. However, some of these findings may not be generalisable to other Indian states and union territories owing to differences in cultural and social factors, and further multi-centre studies that do not rely solely on clinic populations are needed to gain insight to help inform a strategic response at the national level. In conclusion, this study highlights significant gaps in the level of understanding of adult patients regarding the fundamental aspects of asthma and its management in Vellore district and some gaps in basic training for primary care physicians in the diagnosis and management of asthma. The data call for multi-pronged strategies including culturally tailored and targeted supportive interventions towards improving asthma care, as well as provision of free or subsidized treatment for those economically deprived. Furthermore, sustainable practical and clinically orientated training initiatives are needed for primary care physicians. IW was involved in study design, data analysis and was lead for drafting the manuscript. JD was the primary researcher and was involved in data analysis and was co-lead in drafting the manuscript. DJC and MTK were principal investigators and led study design, data interpretation and contributed to drafting the manuscript. AM was involved in data interpretation and contributed to drafting the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. IW and JD accessed and verified the data. We would like to acknowledge the UK R&I Global Challenges Research Fund via Institute of Global Innovation, University of Birmingham, UK, funding the research reported in this paper. We thank all interviewees who gave up their time to share their views and experiences with us. In the past 36 months, the team have received funds to conduct the study reported in the manuscript from the Institute for Global Innovation, University of Birmingham, UK. Dr Adel H Mansur has received personal and institutional funds for talks, advisory board meeting attendance, and educational grants from Astrazeneca, GSK, Novartis, BI, Chiesi, Teva, and Sanofi. Research ethics approval for the study was secured from the Universities of Birmingham (ERN_21_0069) and Christian Medical College, Vellore (IRB Min No. 14029).

Introduction Work-related asthma accounts for ≥25% of asthma in working-age populations, though the relationship between work exposures and symptoms is frequently missed, leading to poor health and employment outcomes. We hypothesised that inhalable exposures at work are associated with poor asthma control in severe asthma (SA).Methods We searched the Birmingham (UK) Regional NHS SA Service clinical database (n=1453 records; 1 March 2004 to 1 March 2021) and undertook a cross-sectional study using baseline data collected at diagnosis. We included all employed patients aged 16–64 with documented current occupation (n=504), and collected socio-demographic, general health and asthma-specific data, including Asthma Control Questionnaire 7 (ACQ7) score. The Occupational Asthma Specific Job-Exposure Matrix (OAsJEM) was employed to determine the likelihood of exposure to respiratory sensitisers, irritants, cleaning agents and detergents; associations between exposures and ACQ7 were investigated using binary and multinomial regression.Results Frequently reported occupations were care assistants (7%) and nurses (6%); 197/504 (39%) patients were exposed to an asthmagen, including respiratory sensitisers (30%), airway irritants (38%) and cleaning products/disinfectants (29%). ACQ7 score was available for 372/504 (74%) patients, of whom 14% had adequate control (ACQ7=0–1.5). After adjustment for major confounders there were no significant associations between inhaled asthmagens and ACQ7 score (either as binary or multinomial outcomes).Conclusion JEM-determined workplace exposures to inhaled asthmagens are not associated with asthma control in SA; 29–39% of patients may have current exposure to workplace asthmagens. Routine collection of lifetime occupational data including current job role and level of exposure, in the national asthma registry, would give further insights into this relationship.