Complement System Dysregulation in the Immunopathogenesis of Long COVID: Systematic Evidence Synthesis

<b>Background/Objective:</b> Long COVID is an important cause of disability following SARS-CoV-2 infection; yet, its underlying mechanisms are not completely understood. One proposed mechanism is the long-lasting dysregulation of the immune complement system. This systematic review is the first to summarize the current evidence and evaluate the potential role of long-lasting complement activation in people with long COVID. <b>Methods:</b> A systematic electronic search on PubMed, MEDLINE, CINAHL, and Embase was conducted up to 15 October 2025, to identify studies investigating complement activation in people with the post-COVID-19 condition. The Newcastle-Ottawa Scale was used to evaluate the risk of bias and methodological quality. <b>Results:</b> Among the 247 studies initially identified, eleven met the inclusion criteria, comprising 1435 individuals (age: 48.5 years, 70% females) with long COVID and 1124 controls (age: 43.6 years, 60% females). All studies were of a high quality, with scores ranging from 7 to 8 stars (mean: 7.6 ± 0.5). The activation of the classical complement pathway was investigated in nine studies, whereas the lectin, alternative, and terminal complement pathways were each assessed in three studies. Multiple studies investigated several complement pathways. The results were heterogeneous since several markers of complement activation spanning the classical (C2, C4a, C4b, and C1s-C1INH), alternative (Ba, iC3b, and Factor D), and terminal (C5bC6, C5a, C9, and TCC) pathways were elevated, whereas other markers were not significantly different (C3, C4, and C4d) between patients with/without long COVID. In addition, markers spanning the lectin complement pathway (MBL, and MASP1-C1INH) were not significantly different between individuals with and without long COVID. <b>Conclusions:</b> The current evidence suggests potential long-lasting complement system dysregulation in individuals with long COVID, although the clinical significance remains controversial, due to heterogenous findings. Specific post-COVID symptom clusters, such as fatigue, dyspnea, or brain fog, have been linked to a distinct pattern of complement dysregulation. Substantial methodological heterogeneity, including differences in follow-up periods, complement markers, assessment methods, and control groups, along with the small number of available studies, underscores the need for further research to clarify the mechanisms linking complement dysregulation to long COVID.