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Complement System Dysregulation in the Immunopathogenesis of Long COVID: Systematic Evidence Synthesis
Kin Israel Notarte1, Jesus Alfonso Catahay2, Jacqueline Veronica Velasco3
1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Biomedicines
|February 27, 2026
Summary
Long COVID may involve lasting immune complement system issues, with some activation markers elevated but findings are mixed. Further research is needed to confirm the link between complement dysregulation and long COVID symptoms.
Area of Science:
- Immunology
- Infectious Diseases
- Systematic Review
Background:
- Long COVID is a significant cause of disability following SARS-CoV-2 infection.
- The precise mechanisms underlying Long COVID remain incompletely understood.
- Dysregulation of the immune complement system is a proposed mechanism contributing to Long COVID.
Purpose of the Study:
- To systematically review and synthesize current evidence on complement activation in individuals with Long COVID.
- To evaluate the potential role of long-lasting complement activation in the pathophysiology of Long COVID.
Main Methods:
- A systematic electronic search was conducted across PubMed, MEDLINE, CINAHL, and Embase databases.
- Studies investigating complement activation in post-COVID-19 condition were included up to October 15, 2025.
- The Newcastle-Ottawa Scale was utilized for risk of bias and quality assessment of included studies.
Main Results:
- Eleven high-quality studies involving 1435 Long COVID patients and 1124 controls were analyzed.
- Heterogeneous findings showed elevated markers in classical, alternative, and terminal complement pathways.
- Some complement markers (C3, C4, C4d, MBL, MASP1-C1INH) did not show significant differences between groups.
Conclusions:
- Evidence suggests potential long-lasting complement system dysregulation in Long COVID, but clinical significance is debated due to heterogeneity.
- Specific Long COVID symptom clusters, like fatigue and brain fog, may correlate with distinct complement dysregulation patterns.
- Methodological heterogeneity necessitates further research to elucidate the mechanisms linking complement dysregulation to Long COVID.
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