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C5a elevation in convalescents from severe COVID-19 is not associated with early complement activation markers C3bBbP
Daria Kowalska1, Alicja Kuźniewska1, Yaiza Senent2,3,4
1Department of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland.
Insights
Complement C5a remains elevated in severe COVID-19 patients post-discharge. However, upstream complement pathway activation markers do not correlate, suggesting a non-canonical C5a source in severe disease.
Area of Science:
- Immunology
- Infectious Diseases
- Complement System Biology
Background:
- The complement system, particularly C5a, is implicated in COVID-19 severity.
- Previous research indicated persistently high C5a levels in severely ill patients up to 90 days post-discharge.
Purpose of the Study:
- To investigate which complement pathway (alternative, classical/lectin) drives elevated C5a levels during COVID-19 hospitalization and follow-up.
- To explore the relationship between C5a and upstream complement activation markers in relation to disease severity.
Main Methods:
- Immunoenzymatic assays were used to measure C5a, alternative pathway (AP) marker C3bBbP, and classical/lectin pathway (CP/LP) marker C4d.
- Serial samples from 49 SARS-CoV-2 infected patients with varying disease severity were analyzed during hospitalization and follow-up.
Main Results:
- C3bBbP and C4d levels did not consistently increase with disease severity, unlike C5a.
- Positive correlations between AP/CP/LP markers and C5a were observed in some patient groups.
- Notably, follow-up samples from the most severely ill patients showed the highest C5a levels but lacked correlation with upstream markers.
Conclusions:
- Persistently high C5a levels post-discharge in severe COVID-19 do not clearly correlate with upstream complement activation.
- These findings suggest a potential non-canonical source of C5a in patients experiencing a severe course of COVID-19.
Abstract:
Numerous publications have underlined the link between complement C5a and the clinical course of COVID-19. We previously reported that levels of C5a remain high in the group of severely ill patients up to 90 days after hospital discharge. We have now evaluated which complement pathway fuels the elevated levels of C5a during hospitalization and follow-up. The alternative pathway (AP) activation marker C3bBbP and the soluble fraction of C4d, a footprint of the classical/lectin (CP/LP) pathway, were assessed by immunoenzymatic assay in a total of 188 serial samples from 49 patients infected with SARS-CoV-2. Unlike C5a, neither C3bBbP nor C4d readouts rose proportionally to the severity of the disease. Detailed correlation analyses in hospitalization and follow-up samples collected from patients of different disease severity showed significant positive correlations of AP and CP/LP markers with C5a in certain groups, except for the follow-up samples of the patients who suffered from highly severe COVID-19 and presented the highest C5a readouts. In conclusion, there is not a clear link between persistently high levels of C5a after hospital discharge and markers of upstream complement activation, suggesting the existence of a non-canonical source of C5a in patients with a severe course of COVID-19.
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