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.

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Asthma is a complex disease involving gene and environment interactions (Holgate). Although atopy is a strong predisposing Rationale risk factor for asthma, local tissue susceptibilities also contribute to disease expression (Moffitt). The bronchial epithelium forms the interface with the external environment and is pivotally involved in controlling tissue homeostasis through provision of a physical barrier controlled by tight junction complexes (Swindle et al, 2009). To explain the link between environment exposures and airway vulnerability, our previous studies based on a small number of volunteers have shown that tight junctions are abnormal in asthma. To confirm the previous findings and strengthen the concept of defective epithelial barrier function in asthma, we studied a much bigger population of asthmatics to assess their epithelial barrier integrity and permeability.Non-asthmatic normal and asthmatic subjects were recruited and clinically characterised in accordance with GINA guidelines. Methods:Bronchial brushings were obtained by fibreoptic bronchoscopy following ethical approval and informed consent. Primary bronchial epithelial cells (pBECs) were expanded from brushings then seeded onto collagen I coated porous transwells and differentiated at in vitro an air-liquid interface (ALI) for 3-4 weeks. Transepithelial electrical resistance (TER) was monitored as an indication of tight junction formation and epithelial integrity using a set of chopstick electrodes and a voltohmmeter. Paracellular permeability was quantified by FITC-dextran flux assay.We studied differentiated bronchial epithelial cultures (n=83) grown from bronchial brushings obtained from normal (40) Results:in vitro or asthmatic (n=43) volunteers. Tight junction function assessed by TER measurement was significantly lower in cultures from asthmatic donors compared to normals (median (interquartile range) = 346 (248-536) Ω·cm 428 (340-593) -analysis of the data revealed that 2 versus TER was significantly decreased as a function of disease severity (p<0.05). TER measurements were inversely correlated with permeability to fluorescently conjugated 20 or 4 kDa dextrans indicating alterations to both ionic and macromolecular permeability in asthma.Our results show that the bronchial epithelial barrier in asthma is compromised. This defect may facilitate the passage of low Conclusions: molecular weight allergens and other agents into the airway tissue leading to immune activation and may thus contribute to the end organ expression of asthma. This work suggests that addressing the barrier defect in asthma may offer a novel therapeutic approach for difficult-to-treat asthmatic subjects who fail to respond to conventional therapy. This abstract is funded by:

Rationale: Ex vivo, bronchial epithelial cells from people with asthma are more susceptible to rhinovirus infection caused by deficient induction of the antiviral protein, IFN-b. Exogenous IFN-b restores antiviral activity.Objectives: To compare the efficacy and safety of inhaled IFN-b with placebo administered to people with asthma after onset of cold symptoms to prevent or attenuate asthma symptoms caused by respiratory viruses.Methods: A total of 147 people with asthma on inhaled corticosteroids (British Thoracic Society Steps 2-5), with a history of virus-associated exacerbations, were randomized to 14-day treatment with inhaled IFN-b (n = 72) or placebo (n = 75) within 24 hours of developing cold symptoms and were assessed clinically, with relevant samples collected to assess virus infection and antiviral responses. Measurements and Main Results:A total of 91% of randomized patients developed a defined cold. In this modified intention-to-treat population, asthma symptoms did not get clinically significantly worse (mean change in six-item Asthma Control Questionnaire ,0.5) and IFN-b treatment had no significant effect on this primary endpoint, although it enhanced morning peak expiratory flow recovery (P = 0.033), reduced the need for additional treatment, and boosted innate immunity as assessed by blood and sputum biomarkers. In an exploratory analysis of the subset of more difficult-to-treat, Step 4-5 people with asthma (n = 27 IFN-b; n = 31 placebo), Asthma Control Questionnaire-6 increased significantly on placebo; this was prevented by IFN-b (P = 0.004).Conclusions: Although the trial did not meet its primary endpoint, it suggests that inhaled IFN-b is a potential treatment for virus-induced deteriorations of asthma in difficult-to-treat people with asthma and supports the need for further, adequately powered, trials in this population. Clinical trial registered with www.clinicaltrials.gov (NCT 01126177).

Background-The importance of IL-13 in the asthma paradigm is supported by increased expression in human subjects, particularly in patients with mild-to-moderate asthma. However, the role of IL-13 in severe asthma needs to be further defined.

Matrix stiffening with downstream activation of mechanosensitive pathways is strongly implicated in progressive fibrosis; however, pathologic changes in extracellular matrix (ECM) that initiate mechano-homeostasis dysregulation are not defined in human disease. By integrated multiscale biomechanical and biological analyses of idiopathic pulmonary fibrosis lung tissue, we identify that increased tissue stiffness is a function of dysregulated post-translational collagen cross-linking rather than any collagen concentration increase whilst at the nanometre-scale collagen fibrils are structurally and functionally abnormal with increased stiffness, reduced swelling ratio, and reduced diameter. In ex vivo and animal models of lung fibrosis, dual inhibition of lysyl oxidase-like (LOXL) 2 and LOXL3 was sufficient to normalise collagen fibrillogenesis, reduce tissue stiffness, and improve lung function in vivo. Thus, in human fibrosis, altered collagen architecture is a key determinant of abnormal ECM structure-function, and inhibition of pyridinoline cross-linking can maintain mechano-homeostasis to limit the self-sustaining effects of ECM on progressive fibrosis.

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These results demonstrate that anti-human IL-13 (CAT-354) is a potential therapeutic treatment for allergic airway and oesophageal diseases.