Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study.

There is a strong scientific rationale to use nebulised unfractionated heparin (UFH) in treating patients with COVID-19. This pilot study investigated whether nebulised UFH was safe and had any impact on mortality, length of hospitalisation and clinical progression, in the treatment of hospitalised patients with COVID-19. This parallel group, open label, randomised trial included adult patients with confirmed SARS-CoV-2 infection admitted to two hospitals in Brazil. One hundred patients were planned to be randomised to either "standard of care" (SOC) or SOC plus nebulized UFH. The trial was stopped after randomisation of 75 patients due to falling COVID-19 hospitalisation rates. Significance tests were 1-sided test (10% significance level). The key analysis populations were intention to treat (ITT) and modified ITT (mITT) which excluded (from both arms) subjects admitted to ITU or who died within 24 h of randomisation. In the ITT population (n = 75), mortality was numerically lower for nebulised UFH (6 out of 38 patients; 15.8%) versus SOC (10 out of 37 patients; 27.0%), but not statistically significant; odds ratio (OR) 0.51, p = 0.24. However, in the mITT population, nebulised UFH reduced mortality (OR 0.2, p = 0.035). Length of hospital stay was similar between groups, but at day 29, there was a greater improvement in ordinal score following treatment with UFH in the ITT and mITT populations (p = 0.076 and p = 0.012 respectively), while mechanical ventilation rates were lower with UFH in the mITT population (OR 0.31; p = 0.08). Nebulised UFH did not cause any significant adverse events. In conclusion, nebulised UFH added to SOC in hospitalised patients with COVID-19 was well tolerated and showed clinical benefit, particularly in patients who received at least 6 doses of heparin. This trial was funded by The J.R. Moulton Charity Trust and registered under REBEC RBR-8r9hy8f (UTN code: U1111-1263-3136).

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.

Qualitative Validation of COPD Evidenced Care Pathways in Japan, Canada, England, and Germany: Common Barriers to Optimal COPD Care.

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. A comprehensive and detailed understanding of COPD care pathways from pre-diagnosis to acute care is required to understand the common barriers to optimal COPD care across diverse health systems. Methods: Country-specific COPD care pathways were created for four high-income countries using international recommendations and country-specific guidelines, then populated with published epidemiological, clinical, and economic data. To refine and validate the pathways, semi-structured interviews using pre-prepared discussion guides and country-specific pathway maps were held with twenty-four primary and secondary care respiratory healthcare professionals. Thematic analysis was then performed on the interview transcripts. Results: The COPD care pathway showed broad consistency across the countries. Three key themes relating to barriers in optimal COPD management were identified across the countries: journey to diagnosis, treatment, and the impact of COVID-19. Common barriers included presentation to healthcare with advanced COPD, low COPD consideration, and sub-optimal acute and chronic disease management. COVID-19 has negatively impacted disease management across the pathway but presents opportunities to retain virtual consultations. Structural factors such as insurance and short duration of appointments also impacted the diagnosis and management of COPD. Conclusion: COPD is an important public health issue that needs urgent prioritization. The use of Evidenced Care Pathways with decision-makers can facilitate evidence-based decision making on interventions and policies to improve care and outcomes for patients and reduce unnecessary resource use and associated costs for the healthcare provider/payer.

Nebulised interferon beta-1a (SNG001) in hospitalised COVID-19: SPRINTER Phase III Study

Background Despite the availability of vaccines and therapies, patients are being hospitalised with COVID-19. Interferon-β is a naturally-occurring protein that stimulates host immune responses against most viruses, including SARS-CoV-2. SNG001 is a recombinant interferon-β1a 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 endpoints 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 1.06 [95%CI 0.89, 1.27];p=0.51);time to recovery was 25.0 days in both groups (1.02 [0.81, 1.28];p=0.89). There were no significant SNG001–placebo differences for the key secondary endpoints, with a 25.7% relative risk reduction in progression to severe disease or death (10.7% and 14.4%, respectively;odds ratio 0.71 [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 endpoints analysis suggested that SNG001 may have prevented progression to severe disease. Study registration number: ISRCTN85436698

Understanding the Needs and Priorities of People Living with Persistent Pain and Long-Term Musculoskeletal Conditions during the COVID-19 Pandemic-A Public Involvement Project.

BACKGROUND: Critiques of public involvement (PI) are associated with failing to be inclusive of under-represented groups, and this leads to research that fails to include a diversity of perspectives. AIM: The aim of this PI project was to understand the experiences and priorities of people from three seldom-heard groups whose musculoskeletal pain may have been exacerbated or treatment delayed due to COVID-19. Engaging representatives to report diverse experiences was important, given the goal of developing further research into personalised and integrated care and addressing population health concerns about access and self-management for people with musculoskeletal pain. METHODS: The project was approved via Sheffield Hallam University Ethics but was exempt from further HRA approval. A literature review was conducted, followed by informal individual and group discussions involving professionals and people with lived experience of (a) fibromyalgia pain, (b) those waiting for elective surgery and (c) experts associated with the care home sector. Findings from the literature review were combined with the insights from the public involvement. Resulting narratives were developed to highlight the challenges associated with persistent pain and informed the creation of consensus statements on the priorities for service improvement and future research. The consensus statements were shared and refined with input from an expert steering group. RESULTS: The narratives describe pain as a uniformly difficult experience to share with professionals; it is described as exhausting, frustrating and socially limiting. Pain leads to exclusion from routine daily activities and often resigns people to feeling and being unwell. In all cases, there are concerns about accessing and improving services and critical issues associated with optimising physical activity, functional wellbeing and managing polypharmacy. Exercise and/or mobilisation are important and commonly used self-management strategies, but opportunity and advice about safe methods are variable. Services should focus on personalised care, including self-management support and medication management, so that people's views and needs are heard and validated by health professionals. CONCLUSIONS: More research is needed to explore the most effective pain management strategies, and public involvement is important to shape the most relevant research questions. Health and care systems evaluation is also needed to address the scale of the population health need. The pandemic appears to have highlighted pre-existing shortcomings in holistic pain management.

Understanding the Needs and Priorities of People Living with Persistent Pain and Long-Term Musculoskeletal Conditions during the COVID-19 Pandemic-A Public Involvement Project

Background: Critiques of public involvement (PI) are associated with failing to be inclusive of under-represented groups, and this leads to research that fails to include a diversity of perspectives. Aim: The aim of this PI project was to understand the experiences and priorities of people from three seldom-heard groups whose musculoskeletal pain may have been exacerbated or treatment delayed due to COVID-19. Engaging representatives to report diverse experiences was important, given the goal of developing further research into personalised and integrated care and addressing population health concerns about access and self-management for people with musculoskeletal pain. Methods: The project was approved via Sheffield Hallam University Ethics but was exempt from further HRA approval. A literature review was conducted, followed by informal individual and group discussions involving professionals and people with lived experience of (a) fibromyalgia pain, (b) those waiting for elective surgery and (c) experts associated with the care home sector. Findings from the literature review were combined with the insights from the public involvement. Resulting narratives were developed to highlight the challenges associated with persistent pain and informed the creation of consensus statements on the priorities for service improvement and future research. The consensus statements were shared and refined with input from an expert steering group. Results: The narratives describe pain as a uniformly difficult experience to share with professionals;it is described as exhausting, frustrating and socially limiting. Pain leads to exclusion from routine daily activities and often resigns people to feeling and being unwell. In all cases, there are concerns about accessing and improving services and critical issues associated with optimising physical activity, functional wellbeing and managing polypharmacy. Exercise and/or mobilisation are important and commonly used self-management strategies, but opportunity and advice about safe methods are variable. Services should focus on personalised care, including self-management support and medication management, so that people's views and needs are heard and validated by health professionals. Conclusions: More research is needed to explore the most effective pain management strategies, and public involvement is important to shape the most relevant research questions. Health and care systems evaluation is also needed to address the scale of the population health need. The pandemic appears to have highlighted pre-existing shortcomings in holistic pain management.

Large scale clinical trials: lessons from the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has presented substantial new challenges to clinical and research teams. Our objective was to analyse the experience of investigators and research delivery staff regarding the research response to COVID-19 in order to identify these challenges as well as solutions for future pandemic planning. METHODS: We conducted a survey of diverse research staff involved in delivery of COVID-19 clinical trials across the UK. This was delivered online across centres linked to the NIHR Respiratory Translational Research Collaboration. Responses were analysed using a formal thematic analysis approach to identify common themes and recommendations. RESULTS: 83 survey participants from ten teaching hospitals provided 922 individual question responses. Respondents were involved in a range of research delivery roles but the largest cohort (60%) was study investigators. A wide range of research experiences were captured, including early and late phase trials. Responses were coded into overarching themes. Among common observations, complex protocols without adaptation to a pandemic were noted to have hampered recruitment. Recommendations included the need to develop and test pandemic-specific protocols, and make use of innovations in information technology. Research competition needs to be avoided and drug selection processes should be explicitly transparent. CONCLUSIONS: Delivery of clinical trials, particularly earlier phase trials, in a pandemic clinical environment is highly challenging, and was reactive rather than anticipatory. Future pandemic studies should be designed and tested in advance, making use of pragmatic study designs as far as possible and planning for integration between early and later phase trials and regulatory frameworks.

The Detrimental Clinical Associations of Anxiety and Depression with Difficult Asthma Outcomes

Difficult asthma describes asthma in which comorbidities, inadequate treatment, suboptimal inhaler technique and/or poor adherence impede good asthma control. The association of anxiety and depression with difficult asthma outcomes (exacerbations, hospital admissions, asthma control, etc.) is unclear. This study assessed the clinical associations of anxiety and depression with difficult asthma outcomes in patients with a specialist diagnosis of difficult asthma. Using real-world data, we retrospectively phenotyped patients from the Wessex Asthma Cohort of Difficult Asthma (N = 441) using clinical diagnoses of anxiety and depression against those without anxiety or depression (controls). Additionally, we stratified patients by severity of psychological distress using the Hospital Anxiety and Depression Scale (HADS). We found that depression and/or anxiety were reported in 43.1% of subjects and were associated with worse disease-related questionnaire scores. Each psychological comorbidity group showed differential associations with difficult asthma outcomes. Anxiety alone (7.9%) was associated with dysfunctional breathing and more hospitalisations [anxiety, median (IQR): 0 (2) vs. controls: 0 (0)], while depression alone (11.6%) was associated with obesity and obstructive sleep apnoea. The dual anxiety and depression group (23.6%) displayed multimorbidity, worse asthma outcomes, female predominance and earlier asthma onset. Worse HADS-A scores in patients with anxiety were associated with worse subjective outcomes (questionnaire scores), while worse HADS-D scores in patients with depression were associated with worse objective (ICU admissions and maintenance oral corticosteroid requirements) and subjective outcomes. In conclusion, anxiety and depression are common in difficult asthma but exert differential detrimental effects. Difficult asthma patients with dual anxiety and depression experience worse asthma outcomes alongside worse measures of psychological distress. There is a severity-gradient association of HADS scores with worse difficult asthma outcomes. Collectively, our findings highlight the need for holistic, multidisciplinary approaches that promote early identification and management of anxiety and depression in difficult asthma patients.

Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike–ACE2 Interaction

Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS–Spike protein–ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19. Heparan sulfate (HS) has emerged as a SARS-CoV-2 coreceptor. Pixatimod (PG545), an HS mimetic, inhibits infectivity of multiple variants offering a novel therapeutic approach against COVID-19.

Understanding the needs and priorities of people living with persistent pain and long-term musculoskeletal conditions during the Covid-19 pandemic (preprint)

Background: Critiques of public involvement (PI) are associated with failing to be inclusive of under-represented groups and this leads to research that fails to include a diversity of perspectives. Aim: The aim of this PI project was to understand the experiences and priorities of people from three seldom heard groups whose musculoskeletal pain may have been exacerbated or treatment delayed due to COVID-19. Engaging representatives to report diverse experiences was important, given the goal of developing further research into personalised and integrated care and addressing population health concerns about access and self-management for people with musculoskeletal pain. Methods: : The project was approved via Sheffield Hallam University Ethics but was exempt from further HRA approval. A literature review was conducted followed by informal individual and group discussions involving professionals and people with lived experience of fibromyalgia pain, those waiting for elective surgery and experts associated with the care home sector. Findings from the literature review were combined with the insights from the public involvement. Together, these formed narratives that highlighted the challenges associated with persistent pain and informed the creation of consensus statements on the priorities for service improvement and future research. The consensus statements were shared and refined with input from an expert steering group. Results: : The narratives describe pain as a uniformly difficult experience to share with professionals;it is described as exhausting, frustrating, and socially limiting. Pain leads to exclusion from routine daily activities and often resigns people to feeling and being unwell. In all cases there are concerns about accessing and improving services and critical issues associated with optimising physical activity, functional wellbeing and managing polypharmacy. Exercise and/or mobilisation are important and commonly used self-management strategies but opportunity and advice about safe methods are variable. Services should focus on personalised care including self-management support and medication management so that people’s views and needs are heard and validated by health professionals. Conclusions: : More research is needed to prioritise the most effective pain management strategies and public involvement is important to shape the most relevant research questions. Health and care systems evaluation is needed to address the scale of the population health need. The pandemic appears to have highlighted pre-existing shortcomings in holistic pain management.

Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults.

Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 human challenge model that enables controlled investigation of pathogenesis, correlates of protection and efficacy testing of forthcoming interventions, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study (ClinicalTrials.gov identifier NCT04865237 ; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care. The study's primary objective was to identify an inoculum dose that induced well-tolerated infection in more than 50% of participants, with secondary objectives to assess virus and symptom kinetics during infection. All pre-specified primary and secondary objectives were met. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Eighteen (~53%) participants became infected, with viral load (VL) rising steeply and peaking at ~5 days after inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies per milliliter (median, 95% confidence interval (8.41, 9.53)). Viable virus was recoverable from the nose up to ~10 days after inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected participants, beginning 2-4 days after inoculation, whereas two (11%) participants remained asymptomatic (no reportable symptoms). Anosmia or dysosmia developed more slowly in 15 (83%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs present even in asymptomatic infection. All infected individuals developed serum spike-specific IgG and neutralizing antibodies. Results from lateral flow tests were strongly associated with viable virus, and modeling showed that twice-weekly rapid antigen tests could diagnose infection before 70-80% of viable virus had been generated. Thus, with detailed characterization and safety analysis of this first SARS-CoV-2 human challenge study in young adults, viral kinetics over the course of primary infection with SARS-CoV-2 were established, with implications for public health recommendations and strategies to affect SARS-CoV-2 transmission. Future studies will identify the immune factors associated with protection in those participants who did not develop infection or symptoms and define the effect of prior immunity and viral variation on clinical outcome.

Digital healthcare in COPD management: a narrative review on the advantages, pitfalls, and need for further research.

Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality despite current treatment strategies which focus on smoking cessation, pulmonary rehabilitation, and symptomatic relief. A focus of COPD care is to encourage self-management, particularly during COVID-19, where much face-to-face care has been reduced or ceased. Digital health solutions may offer affordable and scalable solutions to support COPD patient education and self-management, such solutions could improve clinical outcomes and expand service reach for limited additional cost. However, optimal ways to deliver digital medicine are still in development, and there are a number of important considerations for clinicians, commissioners, and patients to ensure successful implementation of digitally augmented care. In this narrative review, we discuss advantages, pitfalls, and future prospects of digital healthcare, which offer a variety of tools including self-management plans, education videos, inhaler training videos, feedback to patients and healthcare professionals (HCPs), exacerbation monitoring, and pulmonary rehabilitation. We discuss the key issues with sustaining patient and HCP engagement and limiting attrition of use, interoperability with devices, integration into healthcare systems, and ensuring inclusivity and accessibility. We explore the essential areas of research beyond determining safety and efficacy to understand the acceptability of digital healthcare solutions to patients, clinicians, and healthcare systems, and hence ways to improve this and sustain engagement. Finally, we explore the regulatory challenges to ensure quality and engagement and effective integration into current healthcare systems and care pathways, while maintaining patients' autonomy and privacy. Understanding and addressing these issues and successful incorporation of an acceptable, simple, scalable, affordable, and future-proof digital solution into healthcare systems could help remodel global chronic disease management and fractured healthcare systems to provide best patient care and optimisation of healthcare resources to meet the global burden and unmet clinical need of COPD.

COVID-19 and the long-term cardio-respiratory and metabolic health complications.

Severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) transmission continues to impact people globally. Whilst the acute symptoms and management strategies are well documented, millions of people globally are experiencing a prolonged and debilitating symptom profile that is reported to last months and even years. COVID-19 is a multi-system disease however the magnitude of the effects and its associated legacy is presently not well understood. Early reports indicate that multidisciplinary approaches between clinical and non-clinical entities are needed to provide effective and rehabilitative patient support pathways and restore pre-COVID-19 quality of life and functional status. Accordingly, this review provides a summary of the impact on cardiovascular, inflammatory, respiratory, and musculoskeletal function following an acute COVID-19 infection along with the prolonged effects of long-COVID.

Biomarker identification using dynamic time warping analysis: a longitudinal cohort study of patients with COVID-19 in a UK tertiary hospital.

OBJECTIVES: COVID-19 is a heterogeneous disease, and many reports have described variations in demographic, biochemical and clinical features at presentation influencing overall hospital mortality. However, there is little information regarding longitudinal changes in laboratory prognostic variables in relation to disease progression in hospitalised patients with COVID-19. DESIGN AND SETTING: This retrospective observational report describes disease progression from symptom onset, to admission to hospital, clinical response and discharge/death among patients with COVID-19 at a tertiary centre in South East England. PARTICIPANTS: Six hundred and fifty-one patients treated for SARS-CoV-2 between March and September 2020 were included in this analysis. Ethical approval was obtained from the HRA Specific Review Board (REC 20/HRA/2986) for waiver of informed consent. RESULTS: The majority of patients presented within 1 week of symptom onset. The lowest risk patients had low mortality (1/45, 2%), and most were discharged within 1 week after admission (30/45, 67%). The highest risk patients, as determined by the 4C mortality score predictor, had high mortality (27/29, 93%), with most dying within 1 week after admission (22/29, 76%). Consistent with previous reports, most patients presented with high levels of C reactive protein (CRP) (67% of patients >50 mg/L), D-dimer (98%>upper limit of normal (ULN)), ferritin (65%>ULN), lactate dehydrogenase (90%>ULN) and low lymphocyte counts (81%

Wave comparisons of clinical characteristics and outcomes of COVID-19 admissions - Exploring the impact of treatment and strain dynamics.

OBJECTIVES: Dexamethasone has now been incorporated into the standard of care for COVID-19 hospital patients. However, larger intensive care unit studies have failed to show discernible improvements in mortality in the recent wave. We aimed to investigate the impacts of these factors on disease outcomes in a UK hospital study. METHODS: This retrospective observational study reports patient characteristics, interventions and outcomes in COVID-19 patients from a UK teaching hospital; cohort 1, pre 16th June-2020 (pre-dexamethasone); cohort 2, 17th June to 30th November-2020 (post-dexamethasone, pre-VOC 202,012/01 as dominant strain); cohort 3, 1st December-2020 to 3rd March-2021 (during establishment of VOC202012/01 as the dominant strain). RESULTS: Dexamethasone treatment was more common in cohorts 2 and 3 (42.7% and 51.6%) compared with cohort 1 (2.5%). After adjusting for risk, odds of death within 28 days were 2-fold lower in cohort 2 vs 1 (OR:0.47,[0.27,0.79],p = 0.006). Mortality was higher cohort 3 vs 2 (20% vs 14%); but not significantly different to cohort 1 (OR: 0.86,[0.64, 1.15],p = 0.308). CONCLUSIONS: The real world finding of lower mortality following dexamethasone supports the published trial evidence and highlights ongoing need for research with introduction of new treatments and ongoing concern over new COVID-19 variants.

Assessing the Acceptability of a Co-Produced Long COVID Intervention in an Underserved Community in the UK.

BACKGROUND: The COVID-19 pandemic has disproportionately affected people from more deprived communities. The experience of Long COVID is similarly distributed but very few investigations have concentrated on the needs of this population. The aim of this project was to co-produce an acceptable intervention for people with Long COVID living in communities recognised as more deprived. METHODS: The intervention was based on a multi-disciplinary team using approaches from sport and exercise medicine and functional rehabilitation. The co-production process was undertaken with a stakeholder advisory group and patient public involvement representation. This study identified participants by postcode and the indices of multiple deprivation (IMD); recruitment and engagement were supported by an existing health and wellbeing service. A virtual 'clinic' was offered with a team of professional practitioners who met participants three times each; to directly consider their needs and offer structured advice. The acceptability of the intervention was based on the individual's participation and their completion of the intervention. RESULTS: Ten participants were recruited with eight completing the intervention. The partnership with an existing community health and wellbeing service was deemed to be an important way of reaching participants. Two men and six women ages ranging from 38 to 73 were involved and their needs were commonly associated with fatigue, anxiety and depression with overall de-conditioning. None reported serious hardship associated with the pandemic although most were in self-employment/part-time employment or were not working due to retirement or ill-health. Two older participants lived alone, and others were single parents and had considerable challenges associated with managing a household alongside their Long COVID difficulties. CONCLUSIONS: This paper presents the needs and perspectives of eight individuals involved in the process and discusses the needs and preferences of the group in relation to their support for self- managed recovery from Long COVID.

Dysregulation of COVID-19 related gene expression in the COPD lung.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection. METHODS: We quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects. RESULTS: ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p = 0.042) and bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = - 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial biopsies compared to HV-ES controls with log2FC of -0.26 (p = 0.033) and - 0.40, (p = 0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p = 0.0051). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD. However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E-06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively). CONCLUSION: This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung. Further studies to understand the impact on clinical course of disease are now required.

Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection carries a substantial risk of severe and prolonged illness; treatment options are currently limited. We assessed the efficacy and safety of inhaled nebulised interferon beta-1a (SNG001) for the treatment of patients admitted to hospital with COVID-19. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2 pilot trial at nine UK sites. Adults aged 18 years or older and admitted to hospital with COVID-19 symptoms, with a positive RT-PCR or point-of-care test, or both, were randomly assigned (1:1) to receive SNG001 (6 MIU) or placebo by inhalation via a mouthpiece daily for 14 days. The primary outcome was the change in clinical condition on the WHO Ordinal Scale for Clinical Improvement (OSCI) during the dosing period in the intention-to-treat population (all randomised patients who received at least one dose of the study drug). The OSCI is a 9-point scale, where 0 corresponds to no infection and 8 corresponds to death. Multiple analyses were done to identify the most suitable statistical method for future clinical trials. Safety was assessed by monitoring adverse events for 28 days. This trial is registered with Clinicaltrialsregister.eu (2020-001023-14) and ClinicalTrials.gov (NCT04385095); the pilot trial of inpatients with COVID-19 is now completed. FINDINGS: Between March 30 and May 30, 2020, 101 patients were randomly assigned to SNG001 (n=50) or placebo (n=51). 48 received SNG001 and 50 received placebo and were included in the intention-to-treat population. 66 (67%) patients required oxygen supplementation at baseline: 29 in the placebo group and 37 in the SNG001 group. Patients receiving SNG001 had greater odds of improvement on the OSCI scale (odds ratio 2·32 [95% CI 1·07-5·04]; p=0·033) on day 15 or 16 and were more likely than those receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment (hazard ratio 2·19 [95% CI 1·03-4·69]; p=0·043). SNG001 was well tolerated. The most frequently reported treatment-emergent adverse event was headache (seven [15%] patients in the SNG001 group and five [10%] in the placebo group). There were three deaths in the placebo group and none in the SNG001 group. INTERPRETATION: Patients who received SNG001 had greater odds of improvement and recovered more rapidly from SARS-CoV-2 infection than patients who received placebo, providing a strong rationale for further trials. FUNDING: Synairgen Research.