Amerikos Argyriou, Alex Robbins, Rachel Scott, Jodie Chalmers, Harrison I W Wright, Robin N Beaumont, Karen T Elvers, Michael N Weedon, Nick A Maskell, David T Arnold, Fergus W Hamilton
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引用次数: 0
Abstract
Background: Pleural infection is associated with marked local and systemic inflammation leading to significant morbidity. It may be possible to therapeutically augment this response and interleukin-6 is a key signalling cascade in inflammatory pathologies.
Methods: We performed a prospective observational study recruiting patients with pleural effusions secondary to infection and measured interleukin-6 in matched pleural fluid and serum (n = 76). We subsequently performed a large-scale, two sample Mendelian Randomisation study (1601 cases and 830,709 controls), using genetic variation at IL6R to proxy the effect of interleukin-6 inhibition on pleural infection and overcome confounding inherent in observational analyses.
Findings: Pleural interleukin-6 levels in infection were 5000-fold higher than matched serum levels (median 72,752 pg/ml vs. 15 pg/ml). Pleural interleukin-6 predicted systemic inflammation (neutrophil count, C- reactive protein), correlated with clinical markers of disease severity (effusion size, pH, glucose), and was strongly associated with length of hospital stay. In Mendelian randomisation analyses, interleukin-6 inhibition was predicted to have a large protective effect on the incidence of infection (OR 0.23; 95% CI 0.14-0.39 per standard deviation decrease in C- reactive protein). The effect size was larger than that seen in COVID-19 and coronary artery disease, where interleukin-6 inhibition has been successful in trials.
Interpretation: Multiple lines of evidence suggest pleural interleukin-6 drives pathology in pleural infection. Targeting interleukin-6 may hold promise and should be considered in randomised trials.
Funding: This study has been funded by the National Institutes of Health and Care Research Bristol Biomedical Research Centre.
EBioMedicineBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍:
eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.