Complement Response to Burn Injury: Systematic Review and Meta-Analysis of Patient and Animal Studies

Patrick P.G. Mulder^1,2,3*Marit van Hooren¹Roland V. Bumbuc^2,3,4,5Carlijn R. Hooijmans⁶H. Ibrahim Korkmaz^2,3,5,7Bouke Boekema^1,2,3*

• ¹Burn Research Lab, Alliance of Dutch Burn Care, Netherlands, Beverwijk, Netherlands
• ²Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC, VU University, Amsterdam, Netherlands
• ³Amsterdam Movement Sciences, Tissue Function and Regeneration, Amsterdam, Amsterdam, Netherlands
• ⁴Computational Science Lab, Informatics Institute, University of Amsterdam, UvA - LAB42, Amsterdam, Netherlands
• ⁵Department of Molecular Cell Biology and Immunology, AII, Amsterdam UMC, location VUmc, Amsterdam, Netherlands
• ⁶Meta-Research Team, Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, Netherlands
• ⁷Alliance of Dutch Burn Care, Burn Center and Department of Plastic and Reconstructive Surgery, Red Cross Hospital, Beverwijk, Netherlands

Background: Burns often induce a profound inflammatory response that contributes to immune dysfunction, tissue damage, and adverse clinical outcomes. Activation of the complement system plays a crucial role in this response, yet findings across different studies are heterogeneous and lack quantitative synthesis. Therefore, we performed a systematic review and meta-analysis to characterize the overall and temporal dynamics of complement activation following burn injury. Methods: PubMed and Embase were searched on February 20th, 2025, for human and animal studies reporting quantitative data on complement factors after cutaneous burn injury. Meta-analyses were conducted for the reported outcomes. Subgroup analyses were performed for predefined time intervals (post burn days 0-1, 2-4, 5-9, 10-14, 15-21, versus >21). Risk of bias was assessed using SYRCLE and ROBANS-II tools. Results: A total of 110 studies were included in the review, of which 73 were eligible for meta-analysis. The included studies encompassed diverse animal models and human patient cohorts with wide variation in burn size, depth, aetiology, and sampling time points. Across both animal and human studies, substantial underreporting of key methodological details resulted in predominantly unclear or high risk of bias, limiting interpretability and reproducibility. Overall analyses revealed significant increases in C3a, C3b, C5a, factor B, and membrane attack complex (MAC), while alternative pathway activity, C3 conversion, C4, and properdin were reduced. Total complement activity and C3 were not significantly altered in overall analysis. Longitudinal analyses demonstrated a dynamic response: total complement, C3, and C4 were markedly reduced during the first 24 hours, followed by normalization and subsequent elevation of C3 from 10 days after injury. Conclusions: Burn injury is associated with a time-dependent alteration of complement activity characterized by early consumption followed by sustained activation that likely contributes to prolonged inflammation and impaired healing. Our findings provide guidance for complement involvement in burn pathology and support further investigation of time-specific complement-targeted therapeutic strategies.