ARDC Research Link Australia

ORCID Profile
Orcid icon. 0000-0002-3890-7201

Current Organisations
University of Oxford , Southern Health NHS Foundation Trust , Royal College of Physicians , Kings College , Imperial College Faculty of Medicine , American University of the Caribbean School of Medicine BV

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Publications

Publication

Control of Confounding and Reporting of Results in Causal Inference Studies. Guidance for Authors from Editors of Respiratory, Sleep, and Critical Care Journals.

Publisher: American Thoracic Society

Date: 2019

DOI: 10.1513/ANNALSATS.201808-564PS

Publication

Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial

Publisher: Elsevier BV

Date: 09-2021

DOI: 10.1016/S0140-6736(21)01744-X

Publication

Treatment Effects of Low-Dose Theophylline Combined With an Inhaled Corticosteroid in COPD

Publisher: Elsevier BV

Date: 06-2010

DOI: 10.1378/CHEST.09-2363

Abstract: Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose theophylline may be of benefit in the treatment of COPD. To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP) (500 microg bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8-12.4 mg/L). In an across-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (P < .05). Additional across-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum chemokine (C-X-C motif) ligand 8/IL-8 (P < .05). Furthermore, within-arm observational data also demonstrated increases in forced midexpiratory flow rate and FEV(1)% predicted (P < .05) following combination treatment only. In an open-label study, low-dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes ninefold (P < .01) compared with FP alone from the same patients with COPD. Combination therapy with an inhaled corticosteroid and low-dose theophylline may attenuate airway inflammation in patients with COPD. clinicaltrials.gov Identifier NCT00241631.

Publication

British Guideline on the Management of Asthma

Publisher: BMJ

Date: 05-2008

DOI: 10.1136/THX.2008.097741

Publication

Dampening of the respiratory cytokine storm is promoted by inhaled budesonide in patients with early COVID-19

Publisher: Cold Spring Harbor Laboratory

Date: 27-10-2021

DOI: 10.1101/2021.10.26.21265512

Abstract: Vaccinations against SARS-CoV-2 are effective in COVID-19. However, with limited vaccine access, vaccine hesitancy and variant breakthroughs, there is still a need for effective and safe early treatments. Two community-based clinical trials of the inhaled corticosteroid, budesonide, have recently been published showing and improvement in patients with COVID-19 treated early with budesonide 1,2 . To understand mechanistically how budesonide was beneficial, inflammatory mediators were assessed in the nasal mucosa of patients recruited to the Steroids in COVID (STOIC 1 ) trial and a cohort of SARS-CoV-2 negative in iduals. Here we show that in early COVID-19, elevation in viral response proteins and Th1 and Th2 inflammation occurs. Longitudinal s ling in the natural course of COVID-19 showed persistently high interferon levels and elevated concentrations of the eosinophil chemokine, CCL11. In patients who deteriorate, the initial nasal mucosal signal is characterised by a marked suppression of the early inflammatory response, with reduced concentrations of interferon and inflammatory cytokines, but elevated eosinophil chemokines. Systemic inflammation remained altered in COVID-19 patients, implying that even after symptom resolution, changes in immunological mediators do not resolve. Budesonide treatment decreased IL-33 and IFN-γ, implying a reduction in epithelial damage and d ening of the interferon response. Budesonide treatment also increased CCL17 concentrations, suggesting an improved T-cell response and significantly alters inflammatory pathways giving further insight into how this treatment can accelerate patient recovery.

Publication

Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial

Publisher: Cold Spring Harbor Laboratory

Date: 12-04-2021

DOI: 10.1101/2021.04.10.21254672

Abstract: Inhaled budesonide has shown efficacy for treating COVID-19 in the community but has not yet been tested in effectiveness trials. We performed a multicenter, open-label, multi-arm, adaptive platform randomized controlled trial involving people aged ≥65 years, or ≥50 years with comorbidities, and unwell ≤14 days with suspected COVID-19 in the community (PRINCIPLE). Participants were randomized to usual care, usual care plus inhaled budesonide (800µg twice daily for 14 days), or usual care plus other interventions. The co-primary endpoints are time to first self-reported recovery, and hospitalization/death related to COVID-19, both measured over 28 days from randomisation and analysed using Bayesian models. The trial opened on April 2, 2020. Randomization to inhaled budesonide began on November 27, 2020 and was stopped on March 31, 2021 based on an interim analysis using data from March 4, 2021. Here, we report updated interim analysis data from March 25, 2021, at which point the trial had randomized 4663 participants with suspected COVID-19. Of these, 2617 (56.1%) tested SARS-CoV-2 positive and contributed data to this interim budesonide primary analysis 751 budesonide, 1028 usual care and 643 to other interventions. Time to first self-reported recovery was shorter in the budesonide group compared to usual care (hazard ratio 1.208 [95% BCI 1.076 – 1.356], probability of superiority 0.999, estimated benefit [95% BCI] of 3.011 [1.134 – 5.41] days). Among those in the interim budesonide primary analysis who had the opportunity to contribute data for 28 days follow up, there were 59/692 (8.5%) COVID-19 related hospitalizations/deaths in the budesonide group vs 100/968 (10.3%) in the usual care group (estimated percentage benefit, 2.1% [95% BCI −0.7% – 4.8%], probability of superiority 0.928). In this updated interim analysis, inhaled budesonide reduced time to recovery by a median of 3 days in people with COVID-19 with risk factors for adverse outcomes. Once 28 day follow up is complete for all participants randomized to budesonide, final analyses of time to recovery and hospitalization/death will be published. (Funded by the National Institute of Health Research/ United Kingdom Research Innovation [MC_PC_19079] PRINCIPLE ISRCTN number, ISRCTN86534580 .)

Publication

Spirometry services in England post-pandemic and the potential role of AI support software: a qualitative study of challenges and opportunities

Publisher: Royal College of General Practitioners

Date: 06-07-2023

DOI: 10.3399/BJGP.2022.0608

Publication

Coordinated nasal mucosa-mediated immunity accelerates recovery from COVID-19

Publisher: Research Square Platform LLC

Date: 14-03-2023

DOI: 10.21203/RS.3.RS-2666607/V1

Abstract: Viral infection due to severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ) induce a dynamic immune environment. Using nasal mucosal s les in 139 participants from the STOIC study (community-based randomised clinical trial for the use of budesonide in early onset SARS-CoV-2, NCT04416399), we applied predefined immune mediator nodes in relation to clinical outcomes and viral burden. Interferon- and chemokine-dominant nodes increased expression as compared to health, validating our modular approach. Next, we demonstrated that an increase in mucosal immunity-like node consisting of CCL13, CCL17, IL-33, among others was associated with a mean 3.7-day quicker recovery with no primary outcome events, irrespective of treatment arm. By day 14 the mucosal node ided into two daughter nodes linked to interferon molecules and was transcriptionally detectable in nasal cavity basal, hillock and ciliated cells (as per public single cell dataset EGAD00001007718). Our data suggest mucosal-associated mediators are key for early symptom resolution of SARS-CoV-2.