Effects of Azithromycin on Blood Inflammatory Gene Expression and Cytokine Production in Sarcoidosis.

INTRODUCTION: In sarcoidosis granulomas, monocyte-derived macrophages are activated by pro-inflammatory cytokines including TNF and IL-6. Current drug treatment for sarcoidosis aims to suppress inflammation but disabling side effects can ensue. The macrolide azithromycin may be anti-inflammatory. We aimed to determine whether treatment with azithromycin affects blood inflammatory gene expression and monocyte functions in sarcoidosis. METHODS: Blood samples were collected from patients with chronic pulmonary sarcoidosis enrolled in a single arm, open label clinical trial who received oral azithromycin 250 mg once daily for 3 months. Whole blood inflammatory gene expression with or without LPS stimulation was measured using a 770-mRNA panel. Phenotypic analysis and cytokine production were conducted by flow cytometry and ELISA after 24h stimulation with growth factors and TLR ligands. mTOR activity was assessed by measuring phosphorylated S6RP. RESULTS: Differential gene expression analysis indicated a state of heightened myeloid cell activation in sarcoidosis. Compared with controls, sarcoidosis patients showed increased LPS responses for several cytokines and chemokines. Treatment with azithromycin had minimal effect on blood gene expression overall, but supervised clustering analysis identified several chemokine genes that were upregulated. At the protein level, azithromycin treatment increased LPS-stimulated TNF and unstimulated IL-8 production. No other cytokines showed significant changes following azithromycin. Blood neutrophil counts fell during azithromycin treatment whereas mononuclear cells remained stable. Azithromycin had no detectable effects on mTOR activity or activation markers. CONCLUSION: Blood myeloid cells are activated in sarcoidosis, but azithromycin therapy did not suppress inflammatory gene expression or cytokine production in blood. TRIAL REGISTRATION: EudraCT 2019-000580-24 (17 May 2019).

Prevalence, risk factors and characterisation of individuals with long COVID using Electronic Health Records in over 1.5 million COVID cases in England.

OBJECTIVES: This study examines clinically confirmed long-COVID symptoms and diagnosis among individuals with COVID in England, aiming to understand prevalence and associated risk factors using electronic health records. To further understand long COVID, the study also explored differences in risks and symptom profiles in three subgroups: hospitalised, non-hospitalised, and untreated COVID cases. METHODS: A population-based longitudinal cohort study was conducted using data from 1,554,040 individuals with confirmed SARS-CoV-2 infection via Clinical Practice Research Datalink. Descriptive statistics explored the prevalence of long COVID symptoms 12 weeks post-infection, and Cox regression models analysed the associated risk factors. Sensitivity analysis was conducted to test the impact of right-censoring data. RESULTS: During an average 400-day follow-up, 7.4% of individuals with COVID had at least one long-COVID symptom after acute phase, yet only 0.5% had long-COVID diagnostic codes. The most common long-COVID symptoms included cough (17.7%), back pain (15.2%), stomach-ache (11.2%), headache (11.1%), and sore throat (10.0%). The same trend was observed in all three subgroups. Risk factors associated with long-COVID symptoms were female sex, non-white ethnicity, obesity, and pre-existing medical conditions like anxiety, depression, type II diabetes, and somatic symptom disorders. CONCLUSIONS: This study is the first to investigate the prevalence and risk factors of clinically confirmed long-COVID in the general population. The findings could help clinicians identify higher risk individuals for timely intervention and allow decision-makers to more efficiently allocate resources for managing long-COVID.

The Effect of Long-Term Azithromycin on Objective and Subjective Cough in Chronic Respiratory Disease: A Systematic Review and Meta-analysis of Randomised Controlled Trials and Noncomparative Studies.

INTRODUCTION: Azithromycin is an effective treatment for various respiratory conditions but its effect on cough is poorly understood. We synthesised data from randomised controlled trials (RCTs) and noncomparative studies (NCT) examining its effect on objective and subjective cough. METHODS: After prospective registration on PROSPERO, we searched MEDLINE, EMBASE, and CENTRAL for both RCTs and NCT trials examining the effect azithromycin on cough in respiratory disease. RESULTS: We identified 1240 studies of which 6 (4 RCTs and 2 NCT studies) were included in the meta-analysis, with a total of 275 patients. Azithromycin was associated with significant improvement in Leicester Cough Questionnaire scores at follow-up when compared to baseline scores (SMD = 0.62 [95% CI 0.12 to 1.12], p = 0.01). However, when only RCTs were synthesised, no significant effect was observed (SMD = 0.12 [95% CI - 0.36 to 0.60], p = 0.62). There was no significant reduction in cough severity VAS score (SMD = - 0.39 [95% CI - 0.92 to 0.14], p = 0.15). There was no significant reduction in objective cough count (SMD = - 0.41 [95% CI - 1.04 to 0.32], p = 0.09). CONCLUSION: Azithromycin therapy improves cough-related quality of life in various chronic respiratory diseases; however, there was no significant effect on cough outcomes when only data from RCTs were synthesised. We believe that to accurately identify which patients whose cough would benefit from azithromycin a large-scale clinical trial of patients with a broad spectrum of respiratory diseases, with sufficiently severe cough, should be undertaken with subgroup analysis of individual disease areas.

Integrated care policy recommendations for complex multisystem long term conditions and long COVID.

The importance of integrated care for complex, multiple long term conditions was acknowledged before the COVID pandemic but remained a challenge. The pandemic and consequent development of Long COVID required rapid adaptation of health services to address the population's needs, requiring service redesigns including integrated care. This Delphi consensus study was conducted in the UK and found similar integrated care priorities for Long COVID and complex, multiple long term conditions, provided by 480 patients and health care providers, with an 80% consensus rate. The resultant recommendations were based on more than 1400 responses from survey participants and were supported by patients, health care professionals, and by patient charities. Participants identified the need to allocate resources to: support integrated care, provide access to care and treatments that work, provide diagnostic procedures that support the personalization of treatment in an integrated care environment, and enable structural consultation between primary and specialist care settings including physical and mental health care. Based on the findings we propose a model for delivering integrated care by a multidisciplinary team to people with complex multisystem conditions. These recommendations can inform improvements to integrated care for complex, multiple long term conditions and Long COVID at international level.

Nebulised interferon beta-1a (SNG001) in the treatment of viral exacerbations of COPD.

BACKGROUND: Respiratory viral infections are major drivers of chronic obstructive pulmonary disease (COPD) exacerbations. Interferon-ß is naturally produced in response to viral infection, limiting replication. This exploratory study aimed to demonstrate proof-of-mechanism, and evaluate the efficacy and safety of inhaled recombinant interferon-ß1a (SNG001) in COPD. Part 1 assessed the effects of SNG001 on induced sputum antiviral interferon-stimulated gene expression, sputum differential cell count, and respiratory function. Part 2 compared SNG001 and placebo on clinical efficacy, sputum and serum biomarkers, and viral clearance. METHODS: In Part 1, patients (N = 13) with stable COPD were randomised 4:1 to SNG001 or placebo once-daily for three days. In Part 2, patients (N = 109) with worsening symptoms and a positive respiratory viral test were randomised 1:1 to SNG001 or placebo once-daily for 14 days in two Groups: A (no moderate exacerbation); B (moderate COPD exacerbation [i.e., acute worsening of respiratory symptoms treated with antibiotics and/or oral corticosteroids]). RESULTS: In Part 1, SNG001 upregulated sputum interferon gene expression. In Part 2, there were minimal SNG001-placebo differences in the efficacy endpoints; however, whereas gene expression was initially upregulated by viral infection, then declined on placebo, levels were maintained with SNG001. Furthermore, the proportion of patients with detectable rhinovirus (the most common virus) on Day 7 was lower with SNG001. In Group B, serum C-reactive protein and the proportion of patients with purulent sputum increased with placebo (suggesting bacterial infection), but not with SNG001. The overall adverse event incidence was similar with both treatments. CONCLUSIONS: Overall, SNG001 was well-tolerated in patients with COPD, and upregulated lung antiviral defences to accelerate viral clearance. These findings warrant further investigation in a larger study. TRIAL REGISTRATION: EU clinical trials register (2017-003679-75), 6 October 2017.

Digitally monitored inhaled therapy: a 'smart' way to manage severe asthma?

INTRODUCTION: One of the fundamental challenges of managing patients with severe asthma is treatment adherence, particularly with inhaled corticosteroids. Adherence is difficult to measure objectively and poor adherence is associated with worse outcomes. In this study, assess the ability of a 'smart' inhaler to record adherence in severe asthma patients and measure the impact of this on asthma control. METHODS: Consecutive consenting patients meeting criteria for biologics had their existing high-dose ICS/LABA//LAMA combination inhaler/s switched to mometasone/indacaterol/glycopyrronium (114/46/136). Routine clinical data, including blood eosinophils, FeNO, and ACQ-6 scores were collected at baseline and at 4 wk. Adherence was then checked on the Propeller Health app, and good adherence was defined as >80% of prescribed usage. Participants were then followed-up at 12 months to record the proportion of patients who were initiated on biologics. RESULTS: 77 patients (mean [SD] age = 50.4 [15.7] years, 67.5% female [n = 52]) participated. 71 participants were able to use the device and 65% (n = 46) of these attained good asthma control and were not initiated on biologics at 12-month follow-up. Both groups demonstrated a significant reduction in ACQ6 score at follow-up (2.81 vs. 1.92, p < 0.001 and 3.05 vs. 2.60, p < 0.001, respectively), but there was no statistically significant difference in improvement between groups. Patients with optimal adherence also demonstrated a significant reduction in median FeNO at follow-up (47 ppb vs. 40 ppb, p = 0.003). CONCLUSIONS: In severe asthma patients, 'smart' inhalers may represent an effective management tool to improve adherence and asthma control, therefore avoiding the need for patients to commence biological therapies.

Telerehabilitation for patients who have been hospitalised with covid-19: a qualitative study.

PURPOSE: The aim of this qualitative study was to explore the views of participants of a group-based, supervised, telerehabilitation programme, following discharge from hospital with Covid-19. This study was part of a single-centre, fast-track (wait-list), randomised, mixed-methods, feasibility trial of telerehabilitation (Registration: Clinicaltrials.gov reference:285205). METHODS: Semi-structured interviews were conducted over a virtual teleconference platform with 10 participants who took part in a telerehabilitation programme following Covid-19 after discharge from an acute hospital. Data were transcribed verbatim and analysed using thematic analysis. RESULTS: Five themes were important from the participant perspective: telerehabilitation programme as part of the Covid-19 journey; the telerehabilitation programme design and delivery; peer aspects; the role of the instructor; and the role of technology and online delivery. CONCLUSIONS: Overall, the telerehabilitation programme was a positive experience for participants. The instructors were central to this positive view as was the group nature of the programme. The group aspect was particularly important in supporting the broader perceived wellbeing gains, such as the sense of enjoyment and reduced social isolation. Several participants would have liked to have continued with the exercises beyond the six-week intervention indicating that the programme could be a way to help people sustain a physically active lifestyle.IMPLICATIONS FOR REHABILITATIONParticipants who were recovering from Covid-19 following hospital admission perceived the telerehabilitation to be a positive experience overall.The group aspect of the telerehabilitation programme was important in supporting the broader perceived wellbeing gains such as the sense of enjoyment and reduced social isolation.Telerehabilitation programmes for Covid-19 may need to include pathways for participants to continue to engage in exercise beyond the time-limited six-week intervention to support ongoing self-management.

Examining the relationship between inflammatory biomarkers during COVID-19 hospitalization and subsequent long-COVID symptoms: A longitudinal and retrospective study.

INTRODUCTION: Long-COVID is a heterogeneous condition with a litany of physical and neuropsychiatric presentations and its pathophysiology remains unclear. Little is known about the association between inflammatory biomarkers, such as interleukin-6 (IL-6) and C-reactive protein (CRP) in the acute phase, and persistent symptoms after hospitalization in COVID-19 patients. METHODS: IL-6, CRP, troponin-T, and ferritin were analyzed at admission for all patients with COVID-19 between September 1, 2020 to January 10, 2021. Survivors were followed up 3-months following hospital discharge and were asked to report persistent symptoms they experienced. Admission data were retrospectively collected. Independent t-tests and Mann-Whitney U tests were performed. RESULTS: In a sample of 144 patients (62.5% male, mean Age 62 years [SD = 13.6]) followed up 3 months after hospital discharge, the commonest symptoms reported were fatigue (54.2%), breathlessness (52.8%), and sleep disturbance (37.5%). In this sample, admission levels of IL-6, CRP and ferritin were elevated. However, those reporting myalgia, low mood, and anxiety at follow-up had lower admission levels of IL-6 (34.9 vs. 52.0 pg/mL, p = .043), CRP (83 vs. 105 mg/L, p = .048), and ferritin (357 vs. 568 ug/L, p = .01) respectively, compared with those who did not report these symptoms. Multivariate regression analysis showed that these associations were confounded by gender, as female patients had significantly lower levels of IL-6 and ferritin on admission (29.5 vs. 56.1, p = .03 and 421.5 vs. 589, p = .001, respectively) and were more likely to report myalgia, low mood and anxiety, when compared to males. CONCLUSIONS: Our data demonstrate that female patients present more often with lower levels of inflammatory biomarkers on admission which are subsequently associated with long-term post-COVID symptoms, such as myalgia and anxiety, in those discharged from hospital with severe COVID-19. Further research is needed into the role of serum biomarkers in post-COVID prognostication.

A randomised phase 2a study to investigate the effects of blocking interleukin-33 with tozorakimab in patients hospitalised with COVID-19: ACCORD-2.

Background: Increased serum interleukin (IL)-33 predicts poor outcomes in patients hospitalised with coronavirus disease 2019 (COVID-19). We examined the efficacy and safety of tozorakimab, a monoclonal antibody that neutralises IL-33, in improving outcomes in ACCORD-2 (EudraCT: 2020-001736-95). Methods: ACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg plus standard of care (SoC) or SoC alone. The primary end-point was time to clinical response (sustained clinical improvement of ≥2 points on the World Health Organization ordinal scale, discharge from hospital or fit for discharge) by day 29. Other end-points included death or respiratory failure, mortality and intensive care unit admission by day 29, and safety. Serum IL-33/soluble stimulated-2 (sST2) complex levels were measured by high-sensitivity immunoassay. Results: Efficacy analyses included 97 patients (tozorakimab+SoC, n=53; SoC, n=44). Median time to clinical response did not differ between the tozorakimab and SoC arms (8.0 and 9.5 days, respectively; HR 0.96, 80% CI 0.70-1.31; one-sided p=0.33). Tozorakimab was well tolerated and the OR for risk of death or respiratory failure with treatment versus SoC was 0.55 (80% CI 0.27-1.12; p=0.26), while the OR was 0.31 (80% CI 0.09-1.06) in patents with high baseline serum IL-33/sST2 complex levels. Conclusions: Overall, ACCORD-2 results suggest that tozorakimab could be a novel therapy for patients hospitalised with COVID-19, warranting further investigation in confirmatory phase 3 studies.

Designing an intervention to help the quitters quit: A qualitative, intervention co-design study.

Objective: E-cigarettes are increasingly being provided by publicly funded stop smoking services. Our objectives were to understand the challenges and establish the means by which services could best support the use and subsequent discontinuation of e-cigarettes for this purpose. Methods: Semi-structured interviews and co-design workshops with service users and providers of a stop smoking service. Results: Thematic analysis was conducted. Interviews identified: 1. a reluctance to use e-cigarettes for cessation, 2. struggle to quit e-cigarettes (dependency, fear of relapse, compensatory "puffing") and 3. service development needs (consistency of approach). Co-design workshops suggested: 1. facilitation of e-cigarette use through understanding previous failed attempts, 2. offering a longer, two-staged approach to tobacco then e-cigarette cessation, careful timing of behavioural strategies and 3. enhanced communication between providers. Conclusions: Our study suggests additional modifications to smoking cessation support measures when e-cigarettes are used for smoking cessation to address the challenges posed by public health guidance: "smokers should switch to vaping and vapers should stop smoking completely". Innovation: Our study is the first to consider experiences of service users and providers about the challenges of using e-cigarettes for cessation; our co-design group of providers informed nine strategies needed to support this approach in practice.

Improving asthma care through implementation of the SENTINEL programme: findings from the pilot site.

Aim: Short-acting ß2-agonist (SABA) overuse adversely impacts asthma-related outcomes and the environment. The SABA rEductioN Through ImplemeNting Hull asthma guidELines (SENTINEL) programme aims to reduce SABA overuse through supported implementation of an adult asthma guideline, which advocates for a SABA-free maintenance and reliever therapy (MART)-preferred treatment where appropriate, across six primary care networks (PCNs) in the UK. We present findings on patient/disease characteristics, asthma prescribing patterns and exacerbation rates from the pilot PCN. Methods: Patients (aged ≥18 years, prescribed at least one inhaled therapy) and their prescribed asthma treatments were characterised using National Health Service data. Asthma treatments and exacerbations were analysed for three periods: 24‒12 months pre-, 12 months pre- and 12 months post-SENTINEL implementation (November 2020‒January 2021). Results: Of the 2571 registered asthma patients, 33.6% (n=864) underwent an asthma review, of whom 44.7% (n=386) were transitioned to MART. Fewer patients were prescribed three or more SABA canisters per year post-implementation in the overall asthma population (45.4% and 46.2% during 24‒12 months and 12 months pre-implementation, respectively, and 23.9% 12 months post-implementation), and in the two subgroups: 1) those who had an asthma review (74.5% and 83.6% during 24‒12 months and 12 months pre-implementation, respectively, and 26.5% post-implementation); and 2) those transitioned to MART following a review (76.4% and 86.5% during 24‒12 months and 12 months pre-implementation, respectively, and 16.3% post-implementation). A higher proportion of patients were exacerbation-free post-implementation in the overall asthma population and in the two subgroups. At least 71.5% of patients transitioned to MART were still prescribed MART 12 months post-implementation, of whom ≥86.7% were SABA-free. Conclusion: SENTINEL implementation led to reduced SABA prescribing, increased inhaled corticosteroid uptake and fewer asthma exacerbations. MART was considered appropriate for ∼50% of reviewed patients, with improved prescribing patterns sustained post-implementation.

Group-based pulmonary telerehabilitation is feasible, safe, beneficial and well-received in patients who have been hospitalised with COVID-19.

Introduction: Coronavirus disease 2019 (COVID-19) has caused worldwide mass hospitalisation. The need for multidisciplinary post-hospitalisation rehabilitation is becoming increasingly apparent, and telerehabilitation has been endorsed. The aim of study was to investigate the feasibility and efficacy of pulmonary telerehabilitation for COVID-19 survivors. Methods: This was a single-centre, mixed-methods, fast-track (wait-list), randomised controlled trial of telerehabilitation for patients who had been hospitalised with COVID-19. 40 patients discharged from two university teaching hospitals in the north of England were recruited. Telerehabilitation consisted of 12 exercise classes, six education events and opportunity for peer support. Patients commenced telerehabilitation 14 days after randomisation in the fast-track group and 56 days after randomisation in the wait-list group. Outcome measures and results: Descriptive and statistical improvements were noted in several clinical outcome measures. Exercise capacity increased from a median (interquartile range) 20 (14-24) sit-to-stand repetitions in 1 min at baseline to 25 (24-30) post-telerehabilitation. Breathlessness rated using the Medical Research Council dyspnoea scale changed from 3.5 (3-4) at baseline to 2 (1.5-3) post-telerehabilitation, with additional favourable outcomes noted in respiratory symptoms measured using numerical rating scales and visual analogue scales (VAS). Quality of life measured using the EuroQol VAS improved from 55 (60-70) units at baseline to 70 (55-80) units following telerehabilitation. Improvements in fatigue (modified Functional Assessment of Chronic Illness Therapy: Fatigue) and mood (Hospital Anxiety and Depression Scale - Depression) were also observed. Natural recovery was observed in the wait-list group prior to receiving telerehabilitation; however, improvements were accelerated by early telerehabilitation in the fast-track group. Conclusions: We have shown that group-based telerehabilitation is feasible, safe, beneficial and well-received in this population.

Nebulised interferon-ß1a (SNG001) in hospitalised COVID-19: SPRINTER phase III study.

Background: Despite the availability of vaccines and therapies, patients are being hospitalised with coronavirus disease 2019 (COVID-19). Interferon (IFN)-ß is a naturally occurring protein that stimulates host immune responses against most viruses, including severe acute respiratory syndrome coronavirus 2. SNG001 is a recombinant IFN-ß1a formulation delivered to the lungs via nebuliser. SPRINTER assessed the efficacy and safety of SNG001 in adults hospitalised due to COVID-19 who required oxygen via nasal prongs or mask. Methods: Patients were randomised double-blind to SNG001 (n=309) or placebo (n=314) once daily for 14 days plus standard of care (SoC). The primary objective was to evaluate recovery after administration of SNG001 versus placebo, in terms of times to hospital discharge and recovery to no limitation of activity. Key secondary end-points were progression to severe disease or death, progression to intubation or death and death. Results: Median time to hospital discharge was 7.0 and 8.0 days with SNG001 and placebo, respectively (hazard ratio (HR) 1.06 (95% CI 0.89-1.27); p=0.51); time to recovery was 25.0 days in both groups (HR 1.02 (95% CI 0.81-1.28); p=0.89). There were no significant SNG001-placebo differences for the key secondary end-points, with a 25.7% relative risk reduction in progression to severe disease or death (10.7% and 14.4%, respectively; OR 0.71 (95% CI 0.44-1.15); p=0.161). Serious adverse events were reported by 12.6% and 18.2% patients with SNG001 and placebo, respectively. Conclusions: Although the primary objective of the study was not met, SNG001 had a favourable safety profile, and the key secondary end-points analysis suggested that SNG001 may have prevented progression to severe disease.

Multi-organ impairment and long COVID: a 1-year prospective, longitudinal cohort study.

OBJECTIVES: To determine the prevalence of organ impairment in long COVID patients at 6 and 12 months after initial symptoms and to explore links to clinical presentation. DESIGN: Prospective cohort study. PARTICIPANTS: Individuals. METHODS: In individuals recovered from acute COVID-19, we assessed symptoms, health status, and multi-organ tissue characterisation and function. SETTING: Two non-acute healthcare settings (Oxford and London). Physiological and biochemical investigations were performed at baseline on all individuals, and those with organ impairment were reassessed. MAIN OUTCOME MEASURES: Primary outcome was prevalence of single- and multi-organ impairment at 6 and 12 months post COVID-19. RESULTS: A total of 536 individuals (mean age 45 years, 73% female, 89% white, 32% healthcare workers, 13% acute COVID-19 hospitalisation) completed baseline assessment (median: 6 months post COVID-19); 331 (62%) with organ impairment or incidental findings had follow-up, with reduced symptom burden from baseline (median number of symptoms 10 and 3, at 6 and 12 months, respectively). Extreme breathlessness (38% and 30%), cognitive dysfunction (48% and 38%) and poor health-related quality of life (EQ-5D-5L < 0.7; 57% and 45%) were common at 6 and 12 months, and associated with female gender, younger age and single-organ impairment. Single- and multi-organ impairment were present in 69% and 23% at baseline, persisting in 59% and 27% at follow-up, respectively. CONCLUSIONS: Organ impairment persisted in 59% of 331 individuals followed up at 1 year post COVID-19, with implications for symptoms, quality of life and longer-term health, signalling the need for prevention and integrated care of long COVID.Trial Registration: ClinicalTrials.gov Identifier: NCT04369807.

STIMULATE-ICP: A pragmatic, multi-centre, cluster randomised trial of an integrated care pathway with a nested, Phase III, open label, adaptive platform randomised drug trial in individuals with Long COVID: A structured protocol.

INTRODUCTION: Long COVID (LC), the persistent symptoms ≥12 weeks following acute COVID-19, presents major threats to individual and public health across countries, affecting over 1.5 million people in the UK alone. Evidence-based interventions are urgently required and an integrated care pathway approach in pragmatic trials, which include investigations, treatments and rehabilitation for LC, could provide scalable and generalisable solutions at pace. METHODS AND ANALYSIS: This is a pragmatic, multi-centre, cluster-randomised clinical trial of two components of an integrated care pathway (Coverscan™, a multi-organ MRI, and Living with COVID Recovery™, a digitally enabled rehabilitation platform) with a nested, Phase III, open label, platform randomised drug trial in individuals with LC. Cluster randomisation is at level of primary care networks so that integrated care pathway interventions are delivered as "standard of care" in that area. The drug trial randomisation is at individual level and initial arms are rivaroxaban, colchicine, famotidine/loratadine, compared with no drugs, with potential to add in further drug arms. The trial is being carried out in 6-10 LC clinics in the UK and is evaluating the effectiveness of a pathway of care for adults with LC in reducing fatigue and other physical, psychological and functional outcomes at 3 months. The trial also includes an economic evaluation which will be described separately. ETHICS AND DISSEMINATION: The protocol was reviewed by South Central-Berkshire Research Ethics Committee (reference: 21/SC/0416). All participating sites obtained local approvals prior to recruitment. Coverscan™ has UK certification (UKCA 752965). All participants will provide written consent to take part in the trial. The first participant was recruited in July 2022 and interim/final results will be disseminated in 2023, in a plan co-developed with public and patient representatives. The results will be presented at national and international conferences, published in peer reviewed medical journals, and shared via media (mainstream and social) and patient support organisations. TRIAL REGISTRATION NUMBER: ISRCTN10665760.

STIMULATE-ICP-Delphi (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways Delphi): Study protocol.

INTRODUCTION: As mortality rates from COVID-19 disease fall, the high prevalence of long-term sequelae (Long COVID) is becoming increasingly widespread, challenging healthcare systems globally. Traditional pathways of care for Long Term Conditions (LTCs) have tended to be managed by disease-specific specialties, an approach that has been ineffective in delivering care for patients with multi-morbidity. The multi-system nature of Long COVID and its impact on physical and psychological health demands a more effective model of holistic, integrated care. The evolution of integrated care systems (ICSs) in the UK presents an important opportunity to explore areas of mutual benefit to LTC, multi-morbidity and Long COVID care. There may be benefits in comparing and contrasting ICPs for Long COVID with ICPs for other LTCs. METHODS AND ANALYSIS: This study aims to evaluate health services requirements for ICPs for Long COVID and their applicability to other LTCs including multi-morbidity and the overlap with medically not yet explained symptoms (MNYES). The study will follow a Delphi design and involve an expert panel of stakeholders including people with lived experience, as well as clinicians with expertise in Long COVID and other LTCs. Study processes will include expert panel and moderator panel meetings, surveys, and interviews. The Delphi process is part of the overall STIMULATE-ICP programme, aimed at improving integrated care for people with Long COVID. ETHICS AND DISSEMINATION: Ethical approval for this Delphi study has been obtained (Research Governance Board of the University of York) as have approvals for the other STIMULATE-ICP studies. Study outcomes are likely to inform policy for ICPs across LTCs. Results will be disseminated through scientific publication, conference presentation and communications with patients and stakeholders involved in care of other LTCs and Long COVID. REGISTRATION: Researchregistry: https://www.researchregistry.com/browse-the-registry#home/registrationdetails/6246bfeeeaaed6001f08dadc/.

It is time to end our love affair with short-acting ß2-agonists in asthma.

In this issue of ERJOR, Noorduynet al. add data to the growing literature showing that SABA overuse in asthma is both common and associated with severe exacerbations. It is time to take note and act to tackle this global issue. https://bit.ly/3BfwhfS.

Investigating the diagnostic utility of high-resolution oesophageal manometry in patients with refractory respiratory symptoms.

BACKGROUND: The interaction between the respiratory and gastrointestinal systems, and the role of the latter in the development of respiratory pathology, has been examined with a focus on gastro-oesophageal reflux disease (GORD). However, little data exists examining the link between oesophageal motility and respiratory disease. AIMS AND OBJECTIVES: In this study, we examined patterns in oesophageal motility using high-resolution oesophageal manometry (HROM) in patients with refractory respiratory symptoms. METHODS: Data were collected retrospectively for all patients that were investigated using HROM at a single centre for refractory respiratory symptoms between January 1st, 2011-December 1st, 2021. Patients were selected for investigation based on airway reflux symptoms, measured by the Hull Airways Reflux Questionnaire (HARQ). RESULTS: 441 patients were investigated with HROM (64% female, mean age = 56.5 [SD = 13.9]). The commonest diagnoses of these patients were Chronic Cough (77%, n = 339), Asthma (10%, n = 44), and Interstitial Lung Disease (7%, n = 29). The prevalence of oesophageal dysmotility was 66% in our cohort. Those with oesophageal dysmotility had significantly higher HARQ scores than those with normal motility (40.6 vs 35.3, p < 0.001) and there was a significant inverse correlation between HARQ scores and distal contractile integral (DCI), a measure of oesophageal contractility. CONCLUSIONS: Two-thirds of patients with refractory respiratory symptoms were found to have oesophageal dysmotility on HROM. These findings suggest motility disorders of the oesophagus may contribute to the development and progression of respiratory disease. This study highlights the need for further prospective study of the relationship between oesophageal dysmotility and respiratory disease.