Background Mepolizumab is effective for a subset of severe asthma patients in reducing exacerbation frequency. Identification of an early marker associated with long-term beneficial clinical response would facilitate better targeting of treatment. We set out to determine the impact of mepolizumab from a clinical, blood inflammatory cell and serum proteomics perspective and identify early changes in patients designated responder/non-responder at one year. Methods We enrolled asthma patients that met criteria to be prescribed mepolizumab. Patients had clinical and blood cell measurements at baseline, 12 and 26 weeks. Serum proteomics (Alamar NULISA, 250 panel) was completed at baseline and 12 weeks. Results 37 patients completed the study (24 and 13 responder and non-responder respectively at 1 year). Both Asthma Control Questionnaire (ACQ)-6 and Severe Asthma Questionnaire (SAQ) improved at 12 and 26 weeks and were driven by the responder group. A reduction in blood eosinophils and basophils was observed. There was a significant elevation of only 2/248 serum proteins, IL5 and CCL24 after 12 weeks mepolizumab treatment, with elevation being driven by the responder and non-responder groups respectively. A 12-week improvement in SAQ was associated with higher odds of response at one year (OR 6.75, 95% CI 1.42–24.30; p=0.015). Conclusions We identified early changes in the clinical and protein profile in patients that go onto have a clinically relevant response to mepolizumab providing opportunities for a more personalised asthma management.

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:In ∼10% of asthma patients, symptoms remain uncontrolled despite maximal treatment, representing an unmet clinical need. The causal variants, genes and pathways underlying genetic risk factors have not been fully elucidated, and it is unclear whether there are unique genetic risk factors for this asthma subtype. Methods:We used electronic healthcare records linked to UK Biobank to identify asthma patients with high treatment burden and/or worse outcomes. We performed a genome-wide association study (GWAS) with this case population and healthy controls. We sought replication for associated (p≤5×10-6) signals in four independent studies (12 152 cases and 32 316 controls). Replicated signals were fine-mapped and linked to genes and pathways. Results:In total, 7681 participants met our case definition and showed enrichment for adult-onset asthma, female gender and higher body mass index compared to asthma individuals not meeting case criteria. GWAS with 7681 cases and 38 405 controls revealed 21 reproducible association signals that had previously been associated with asthma, but had a larger effect size in our study. Variant-to-gene mapping highlighted 85 candidate genes, five of which were considered high confidence (BACH2, D2HGDH, IL1RL1, RPS26, SMAD3). Conclusion:We present the first use of electronic healthcare records in UK Biobank to identify a subtype of asthma enriched for patients with high treatment burden and/or worse outcomes. Our findings support the role of known asthma genes, highlighting genetic risk variants with stronger effect in these groups of patients. The prioritised genes provide potential therapeutic opportunities for this difficult-to-treat patient population.

Background:Early in the COVID-19 pandemic, there was concern about potentially unnecessary antibiotic prescribing in the National Health Service. Procalcitonin testing was being used in some hospitals to guide antibiotic use. This study aimed to investigate the impact of procalcitonin testing on United Kingdom's antibiotic prescribing and health outcomes. Methods:Mixed-methods study comprising quantitative, qualitative and health economic work packages, including a: survey of National Health Service hospitals to understand procalcitonin use retrospective, controlled, interrupted time series analysis of aggregated, organisation-level data, including antibiotic dispensing, hospital activity and procalcitonin testing from acute hospital trusts/hospitals in England/Wales. Primary outcome: change in level and/or trend of antibiotic prescribing rates following introduction of procalcitonin multicentre, retrospective, cohort study of 5960 patients using patient-level clinical data from 11 trusts/health boards to determine the difference in early antibiotic prescribing between COVID-19 patients who did/did not have baseline procalcitonin testing by using propensity score matching. Primary outcome: days of early antibiotic therapy qualitative study exploring the decision-making process around antibiotic use for inpatients with COVID-19 pneumonia to identify the contextual factors, feasibility and acceptability of procalcitonin testing algorithms health economic analysis evaluating the cost-effectiveness of baseline procalcitonin testing using the matched data within a decision-analytic model. Setting:Acute hospital trusts/health boards in England/Wales. Participants:Inpatients ≥ 16 years, admitted to participating trusts/health boards and with a confirmed positive COVID-19 test between 1 February 2020 and 30 June 2020, National Health Service healthcare workers. Results:Early in the COVID-19 pandemic, procalcitonin use was expanded/introduced in many National Health Service hospitals, with variation in guidance and interpretation of results. The number of hospitals using procalcitonin in emergency/acute admissions rose from 17 (11%) to 74/146 (50.7%), and its use in intensive care unit increased from 70 (47.6%) to 124/147 (84.4%). Introduction of procalcitonin testing in emergency departments/acute medical admission units was associated with a statistically significant decrease in antibiotic use, which was not sustained. Patient-level data showed that baseline procalcitonin testing was associated with an average reduction in early antibiotic prescribing of 0.43 days (95% confidence interval: 0.22 to 0.64 days, p < 0.001) and a reduction of 0.72 days (95% confidence interval: 0.06 to 1.38 days, p = 0.03) in total antibiotic prescribing, with no increased mortality/hospital length of stay. Interviews revealed concerns about secondary bacterial infections that led to increased antibiotic prescribing in COVID-19 patients. As experience increased, clinician's ability to distinguish between COVID-19 alone and bacterial coinfections increased. Antibiotic prescribing decisions were influenced by factors such as senior support, situational factors and organisational influences. The health economic analysis concluded that baseline procalcitonin testing was more likely to be cost-effective than not, albeit with some uncertainty. Conclusion:Baseline procalcitonin testing appears to have been an effective antimicrobial stewardship tool during the first wave of the pandemic, reducing antibiotic prescribing without evidence of harm. Limitations:The retrospective, hospital record-based studies were limited by missing data, incorrectly recorded information and lack of randomisation. Interviews with clinicians were conducted more than a year after the first wave, potentially resulting in recall bias. Future work:This study highlights the need for adaptive, inclusive, wide-reaching trials of infection diagnostics and implementation research to assess clinical utility before routine introduction into clinical practice. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132254.

Background:Respiratory diseases cause substantial morbidity and mortality in low- and middle-income countries (LMICs). Registries in high-income countries have significantly advanced the understanding of lung diseases. This feasibility study aimed to establish a registry of patients with suspected respiratory disease at a major teaching hospital in Addis Ababa, Ethiopia. Methods:A prospective hospital-based registry was established at Tikur Anbessa Specialized Hospital (TASH) for patients aged ≥18 years with respiratory disease. The registry collected demographic, clinical, and spirometric data. Results:The registry captured data from 285 participants. Of these, 132 (46%) were diagnosed with asthma and 41 (14%) with chronic obstructive pulmonary disease (COPD). Among patients with asthma, the median pre-bronchodilator forced expiratory volume in one second (FEV1) was 0.94 L, with a percent predicted of 39% (IQR: 29-55). Post-bronchodilator FEV1 increased to a median of 1.20 L, percent predicted 54% (IQR: 38-70), with a median percentage change in FEV1 of 27%. Asthma prevented 54 participants (41%) from performing basic life activities. According to the Global Initiative for Asthma (GINA) symptom assessment tool, only 6 patients (4%) had controlled asthma.Among patients with COPD, the median pre-bronchodilator FEV1 was 0.97 L, percent predicted 43% (IQR: 34-61). Post-bronchodilator FEV1 was 1.02 L, percent predicted 46% (IQR: 37-64), with a median percentage change in FEV1 of 6% (IQR: 2-8). Conclusion:This study demonstrates that establishing a respiratory patient registry in Ethiopia is feasible. Such registries represent an important first step toward defining disease burden, identifying risk factors, improving treatment, and ultimately enabling tailored clinical trials to advance respiratory care in the country.

Aim To integrate the quantitative and qualitative data collected as part of the PEACH (Procalcitonin: Evaluation of Antibiotic use in COVID-19 Hospitalised patients) study, which evaluated whether procalcitonin (PCT) testing should be used to guide antibiotic prescribing and safely reduce antibiotic use among patients admitted to acute UK National Health Service (NHS) hospitals.Design Triangulation to integrate quantitative and qualitative data.Setting and participants Four data sources in 148 NHS hospitals in England and Wales including data from 6089 patients.Method A triangulation protocol was used to integrate three quantitative data sources (survey, organisation-level data and patient-level data: data sources 1, 2 and 3) and one qualitative data source (clinician interviews: data source 4) collected as part of the PEACH study. Analysis of data sources initially took place independently, and then, key findings for each data source were added to a matrix. A series of interactive discussion meetings took place with quantitative, qualitative and clinical researchers, together with patient and public involvement (PPI) representatives, to group the key findings and produce seven statements relating to the study objectives. Each statement and the key findings related to that statement were considered alongside an assessment of whether there was agreement, partial agreement, dissonance or silence across all four data sources (convergence coding). The matrix was then interpreted to produce a narrative for each statement.Objective To explore whether PCT testing safely reduced antibiotic use during the first wave of the COVID-19 pandemic.Results Seven statements were produced relating to the PEACH study objective. There was agreement across all four data sources for our first key statement, ‘During the first wave of the pandemic (01/02/2020-30/06/2020), PCT testing reduced antibiotic prescribing’. The second statement was related to this key statement, ‘During the first wave of the pandemic (01/02/2020-30/06/2020), PCT testing safely reduced antibiotic prescribing’. Partial agreement was found between data sources 3 (quantitative patient-level data) and 4 (qualitative clinician interviews). There were no data regarding safety from data sources 1 or 2 (quantitative survey and organisational-level data) to contribute to this statement. For statements three and four, ‘PCT was not used as a central factor influencing antibiotic prescribing’, and ‘PCT testing reduced antibiotic prescribing in the emergency department (ED)/acute medical unit (AMU),’ there was agreement between data source 2 (organisational-level data) and data source 4 (interviews with clinicians). The remaining two data sources (survey and patient-level data) contributed no data on this statement. For statement five, ‘PCT testing reduced antibiotic prescribing in the intensive care unit (ICU)’, there was disagreement between data sources 2 and 3 (organisational-level data and patient-level data) and data source 4 (clinician interviews). Data source 1 (survey) did not provide data on this statement. We therefore assigned dissonance to this statement. For statement six, ‘There were many barriers to implementing PCT testing during the first wave of COVID-19’, there was partial agreement between data source 1 (survey) and data source 4 (clinician interviews) and no data provided by the two remaining data sources (organisational-level data and patient-level data). For statement seven, ‘Local PCT guidelines/protocols were perceived to be valuable’, only data source 4 (clinician interviews) provided data. The clinicians expressed that guidelines were valuable, but as there was no data from the other three data sources, we assigned silence to this statement.Conclusion There was agreement between all four data sources on our key finding ‘during the first wave of the pandemic (01/02/2020-30/06/2020), PCT testing reduced antibiotic prescribing’. Data, methodological and investigator triangulation, and a transparent triangulation protocol give validity to this finding.Trial registration number ISRCTN66682918.

OBJECTIVES:During the COVID-19 pandemic, individuals from non-White and with poorer socio-economic status (SES) had higher rates of mortality than their counterparts. The hypothesis that these individuals had more severe respiratory failure at the time of first presentation to hospital was tested. STUDY DESIGN:Observational cross-sectional study using routinely collected physiological measurements. METHODS:The study population consisted of all individuals admitted to Nottingham University Hospitals NHS Trust from 1 February 2020 and 31 December 2021. Severity of respiratory failure was measured by the oxygen saturation fraction ratio (SFR, oxygen%/inspired oxygen concentration%). RESULTS:Patients from the areas of highest quintiles of deprivation had an adjusted SFR of 12.6 (95 % confidence intervals [CI]: 7.4 to 17.8) units lower than patients from areas of the lowest deprivation. Patients from an Asian ethnic group has a lower SFR than those from a White ethnic group (-10.9 units; 95 % CI: -19.1 to -2.7). Sensitivity analysis adjusting for the measurement error of pulse oximetry by ethnicity increased this differential for Asian and Black ethnic groups. CONCLUSIONS:These data suggest that individuals from both non-White ethnic groups and poorer SES are sicker at the time of presentation to hospital with COVID-19 infection. Public health strategies are required to understand these observations and counter them with appropriate interventions. These may vary from proximal factors such as enhanced access to healthcare to more distal ones including building trust in modern medical treatments. These data are from one centre and hence should be interpretated cautiously particular with generalisability to other healthcare settings.

Medical practice is built on the foundations of evidence-based medicine. Hence, the more common the clinical intervention, the more comprehensive the evidence on which that intervention should be based. Although the widespread adoption of a national early warning score in the UK has led to improvements in the delivery of care, it should be considered as providing a foundation that can be refined and developed, and there is still a need for critical reflection and evaluation of early warning scores, particularly for individuals with chronic respiratory disease, in order to optimise patient monitoring, predict deterioration and guide intervention.

Background:Understanding the reasons for delays in leaving hospital once an in-patient is considered ready for discharge is important to inform the development of interventions to improve patient flow through resource-stressed healthcare systems. Aims:To identify risk factors for delayed discharge from hospital during the COVID-19 pandemic. Methods:The study population was all patients admitted with COVID-19 infection from February 2020 to September 2021 to a large UK teaching hospital. Results:Data were available from 7929 admission events with a median delay of 0.20 days from being considered medically safe for discharge and the discharge date. Age older than 60 years (+2.23 days), White ethnicity (+1.58 days compared to SE Asian), living in an area of increased affluence (+0.13 days per decile decrease in deprivation) and having two or more comorbidities (+1.82 days; compared to no comorbidities) were associated with delayed discharge.There was a total potential saving of over 22,000 bed-days if all patients had been discharged when they were considered medically safe. Conclusions:Early identification of patients at an increased risk of a delayed discharge may allow development of appropriate anticipatory interventions, and inform policymakers to help identify and minimise bottlenecks at the institutional level.

Few studies have explored the variability of the oxygen-haemoglobin dissociation curve in vivo.96,428 blood gas measurements were obtained (80,376 arterial, 6,959 venous) from a cohort of 7,656 patients who were admitted to a large UK teaching hospital between 1 February 2020 and 31 December 2021 for a Covid-19 related admission with a positive PCR. There was consistent variation of the distribution of the oxygen-haemoglobin curve across most oxygen saturation strata with typical values at 91-92% saturation (mean 8.1kPa, standard deviation sd 0.6 kPa or 60.8mmHg sd 4.5mmHg), with the exception of the highest strata of oxygen saturation of 99-100% (mean 17.7 kPa, sd 8.1kPa or 132mmHg sd 60.8).The higher oxygen partial pressures at higher oxygen saturations are a concern in view of the increased mortality observed in RCTs of higher oxygen saturation targets. However, the observational study design precludes any attribution of causality.

ABSTRACT Background Chest radiographs are generally used for diagnostic purposes. They also have potential to quantify disease severity. This analysis tested the hypothesis that there was an association between chest radiograph opacification and measures of respiratory physiological status and systemic inflammation in patients with Covid‐19 infection. Methods Data on chest radiograph opacification were compared with concurrent measures of oxygen requirements and saturation and serum C‐reactive protein. Results Data were available from 628 individuals. The median opacification on chest radiographs was 20% (interquartile range 5–45). This was associated both SFR (oxygen saturation/supplementary oxygen) with an r value of −0.38 (95% confidence intervals CI: −0.45 to −31, Pearson's correlation coefficient) and CRP (+0.33; 95% CI: +0.24 to +0.41, Pearson's correlation coefficient). Conclusion Chest radiograph opacification scores are associated with both respiratory physiology status and systemic inflammation levels in patients with Covid‐19 infection.

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.

Aim To determine the frequency with which the National Early Warning Score-2 (NEWS-2) fails to detect physiological deterioration preceding in-hospital cardiac arrest (IHCA). Methods We conducted a retrospective observational study of all adult patients (age ≥ 18) who had suffered an IHCA between 1st July 2019 and 31st December 2021 in two large acute hospitals located in an urban centre (Nottingham, UK). Clinical observations and case notes were examined for the period leading up to IHCA events to determine if there was evidence of physiological deterioration which warranted an urgent patient assessment, whether NEWS-2 was triggered, and whether an urgent assessment actually took place. Results Urgent assessment was indicated in the lead-up to 126/374 (33.7 %) IHCA cases, and NEWS-2 failed to trigger in 20 of these cases (15.9 %). An urgent assessment took place in 89/106 (84.0 %) cases where NEWS-2 was triggered, and 13/20 (65.0 %) cases where NEWS-2 was not triggered, with the difference in proportions being statistically significant (p = 0.048). Half of cases in which NEWS-2 missed a physiological deterioration were related to a new or rising oxygen requirement. Conclusions A significant proportion of IHCA events are preceded by clinically important abnormalities in vital signs which are not detected by NEWS-2. This may be a causative factor in some failure-to-rescue events.