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Background: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19., Methods: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012., Findings: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug., Interpretation: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19., Funding: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial., Competing Interests: Declaration of interests JDC reports grants and personal fees from AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Gilead Sciences, Grifols, Insmed, Janssen, Novartis, and Zambon. CB reports grants from the UK National Institute for Health and Care Research Biomedical Research Centre during the conduct of the study; grants and personal fees from GSK, AstraZeneca, Chiesi, Boehringer-Ingelheim, Genentech, Roche, Sanofi, Regeneron, Merck, TEVA, Mologic, 4DPharma, and Novartis. AART reports grants and personal fees from British Heart Foundation and Actelion Pharmaceuticals. JU reports personal fees from Gilead Sciences and ViiV Healthcare and from Celltrion; and is supported by the UK Medical Research Council (MR/T023791/1). DPSD reports grants and personal fees from GSK, Vir Biotechnology, AstraZeneca, and Boehringer-Ingelheim. ASm has received non-financial support for clinical trial work from AstraZeneca, GSK, Chiesi, and Oncimmune; and has done consultancy work with AstraZeneca and GSK. MP reports non-financial support for clinical trial work from AstraZeneca, GSK, Chiesi, and Oncimmune and consultancy work with AstraZeneca and GSK. All other authors report no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, inflammation and thrombosis in coronavirus disease 2019 (COVID-19) and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients., Methods: Neutrophils were isolated from healthy volunteers (n=9) and hospitalised patients with COVID-19 at the acute stage (n=39) and again at 3-4 months post-acute sampling (n=7). NETosis was measured by SYTOX green assays., Results: Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to lipopolysaccharide (LPS) compared to cells from healthy control subjects. A subset of patients was captured at follow-up clinics (3-4 months post-acute sampling), and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and phorbol myristate acetate (PMA)-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death., Conclusion: Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19., Competing Interests: Conflict of interest: R. Dowey has nothing to disclose. Conflict of interest: J. Cole has nothing to disclose. Conflict of interest: A.A.R. Thompson has nothing to disclose. Conflict of interest: R.C. Hull has nothing to disclose. Conflict of interest: C. Huang has nothing to disclose. Conflict of interest: J. Whatmore has nothing to disclose. Conflict of interest: A. Iqbal has nothing to disclose. Conflict of interest: K.L. Bradley has nothing to disclose. Conflict of interest: J. McKenzie has nothing to disclose. Conflict of interest: A. Lawrie has nothing to disclose. Conflict of interest: A.M. Condliffe has nothing to disclose. Conflict of interest: E. Kiss-Toth has nothing to disclose. Conflict of interest: I. Sabroe has nothing to disclose. Conflict of interest: .R. Prince has nothing to disclose., (Copyright ©The authors 2022.)

Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. Neutrophil responses to infection are dysregulated in diabetes, predominantly mediated by persistent hyperglycaemia; the chief biochemical abnormality in T1D and T2D. Therapeutically enhancing host immunity in diabetes to improve infection resolution is an expanding area of research. Individuals with diabetes are also at an increased risk of severe coronavirus disease 2019 (COVID-19), highlighting the need for re-invigorated and urgent focus on this field. The aim of this review is to explore the breadth of previous literature investigating neutrophil function in both T1D and T2D, in order to understand the complex neutrophil phenotype present in this disease and also to focus on the development of new therapies to improve aberrant neutrophil function in diabetes. Existing literature illustrates a dual neutrophil dysfunction in diabetes. Key pathogen handling mechanisms of neutrophil recruitment, chemotaxis, phagocytosis and intracellular reactive oxygen species (ROS) production are decreased in diabetes, weakening the immune response to infection. However, pro-inflammatory neutrophil pathways, mainly neutrophil extracellular trap (NET) formation, extracellular ROS generation and pro-inflammatory cytokine generation, are significantly upregulated, causing damage to the host and perpetuating inflammation. Reducing these proinflammatory outputs therapeutically is emerging as a credible strategy to improve infection resolution in diabetes, and also more recently COVID-19. Future research needs to drive forward the exploration of novel treatments to improve infection resolution in T1D and T2D to improve patient morbidity and mortality., Competing Interests: SH undertakes consultancy for Eli Lilly, Sanofi Aventis, NovoNordisk, Zealand Pharma, and have been on speaker panels for NovoNordisk and Astra Zeneca. These companies’ products have effects on hypoglycaemia when treating individuals with diabetes and are therefore related to this paper. AI has consulted for OrbiMed LLC and received educational grant support from Sanofi S.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dowey, Iqbal, Heller, Sabroe and Prince.)