Classical Pathway Persistent Complement Activation is Associated with Specific Symptoms in Individuals with Post-COVID-19 Condition: A Case-Control Study

The complement system is a crucial part of the immune system. The role of complement activation in post-COVID-19 condition is still not conclusive. We present a case-control study investigating long-lasting complement hyperactivation in COVID-19 survivors with/without post-COVID-19 condition. A case-control (2:1 design) study was performed. Concentration levels of four proteins from classical complement pathway (C3,C4,C5,C7) as well as total hemolitycal complement (CH50) activity were obtained from blood samples in group of survivors with post-COVID-19 condition and in a comparison group of survivors without post-COVID-19 condition matched by age, sex, and vaccination status. Post-COVID-19 condition was defined when individuals self-reported at least one of these post-COVID symptoms: fatigue, arthralgia, myalgia, memory problems, newly onset headache, or palpitations. Fifty-seven (56.1% women, age: 46.5, SD: 9.0 years) survivors with post-COVID-19 condition and 27 (55.5% women, age: 46.5, SD: 11.5 years) survivors without post-COVID-19 condition were evaluated 1.7 (SD 1.2) and 2.0 (SD 1.7) years after SARS-CoV-2 infection, respectively. Overall, the results did not reveal differences in complement protein levels and CH50 activity between survivors with or without post-COVID-19 condition. Patients reporting post-COVID fatigue exhibited lower C3 levels (P=0.025) than those without reporting post-COVID fatigue whereas survivors with post-COVID dyspnea reported lower levels of C3 (P=0.001), C5 (P=0.015) and C7 (P=0.030) proteins than those survivors without post-COVID dyspnea. This explorative case-control study did not observe overall complement activation from classical pathway in survivors with post-COVID-19 condition up to two years after. Some complement proteins were elevated in individuals with specific post-COVID symptoms, e.g., fatigue or dyspnea.