Association between circulating inflammatory biomarkers and functional outcome or perihaematomal oedema after ICH: a systematic review & meta-analysis [version 2; peer review: 1 approved, 3 approved with reservations]

Abstract

Background Currently, there are no specific medical treatments for intracerebral haemorrhage (ICH), but the inflammatory response may provide a potential route to treatment. Given the known effects of acute brain injury on peripheral immunity, we hypothesised that inflammatory biomarkers in peripheral blood may be associated with clinical outcome following ICH, as well as perihaematomal oedema (PHO), which is an imaging marker of the neuroinflammatory response. Methods We searched OVID Medline and EMBASE on 07 April 2021 for studies of humans with ICH measuring an inflammatory biomarker in peripheral blood and PHO or clinical outcome. Risk of bias was assessed both by using a scale comprising features of the Newcastle-Ottawa Assessment Scale, STROBE-ME and REMARK guidelines, and for studies included in meta-analysis, also by the QUIPS tool.We used random effects meta-analysis to pool standardised mean differences (SMD) if ≥1 study quantified the association between identical biomarkers and measures of PHO or functional outcome. Results Of 8,615 publications, 16 examined associations between 21 inflammatory biomarkers and PHO (n=1,299 participants), and 93 studies examined associations between ≥1 biomarker and clinical outcome (n=17,702 participants). Overall, 20 studies of nine biomarkers (n=3,199) met criteria for meta-analysis of associations between inflammatory biomarkers and clinical outcome. Death or dependency (modified Rankin Scale (mRS) 3‒6) 90 days after ICH was associated with higher levels of fibrinogen (SMD 0.32; 95%CI [0.04, 0.61]; p=0.025), and high mobility group box protein 1 (HMGB1) (SMD 1.67; 95%CI [0.05, 3.30]; p=0.04). Higher WBC was associated with death or dependency at 90 days (pooled SMD 0.27; 95% CI [0.11, 0.44]; p=0.001; but the association was no longer significant when the analysis was restricted to studies with a low risk of bias (pooled SMD 0.22; 95% CI -0.04-0.48). Higher CRP seemed to be associated with death or dependency at 90 days (pooled SMD 0.80; 95% CI [0.44, 1.17]; p<0.0001) but this association was no longer significant when adjusted OR were pooled (OR 0.99 (95% CI 0.98-1.01)). Conclusions Higher circulating levels of, fibrinogen and HMGB1 are associated with poorer outcomes after ICH. This study highlights the clinical importance of the inflammatory response to ICH and identifies additional research needs in determining if these associations are mediated via PHO and are potential therapeutic targets. Registration PROSPERO (CRD42019132628; 28/05/2019).

Keywords

• Intracerebral Haemorrhage
• Inflammation
• Perihematomal Oedema
• Biomarkers
• Neuroimmunology
• Stroke
• eng