Complement C3 identified as a unique Risk Factor for Disease Severity among Young COVID-19 Patients in Wuhan

Cheng, W.; Hornung, R.; Xu, K.; Li, J.

Background Given that a substantial proportion of the subgroup of COVID-19 patients that face a severe disease course are younger than 60 years, it is critical to understand the disease-specific characteristics of young COVID-19 patients. Risk factors for a severe disease course for young COVID-19 patients and possibly non-linear influences remain unknown. Methods Data of COVID-19 patients with clinical outcome in a designated hospital in Wuhan, China, collected retrospectively from Jan 24th to Mar 27th, were analyzed. Clinical, demographic, treatment and laboratory data were collected from patients' medical records. Uni- and multivariable analysis using logistic regression and random forest, with the latter allowing the study of non-linear influences, were performed to investigate and exploit the clinical characteristics of a severe disease course. Results A total of 762 young patients (median age 47 years, interquartile ranges [IQR] 38 - 55, range 16 - 60; 55.9% female) were included, as well as 714 elderly patients as a comparison group. Among the young patients, 362 (47.5%) had a severe/critical disease course and the mean age was significantly higher in the severe subgroup than in the mild subgroup (59.3 vs. 56.0, Student's t-test: p < 0.001). The uni- and multivariable analysis suggested that several covariates such as elevated levels of ASS, CRP and LDH, and decreased lymphocyte counts are influential on disease severity independent of age. Elevated levels of complement C3 (odds ratio [OR] 15.6, 95% CI 2.41-122.3; p=0.039) are particularly associated with the risk for the development of severity specifically in young patients, where no such influence seems to exist for elderly patients. Additional analysis suggests that the influence of complement C3 in young patients is independent of age, gender, and comorbidities. Variable importance values and partial dependence plots obtained using random forests delivered additional insights, in particular indicating non-linear influences of risk factors on disease severity. Conclusion In young patients with COVID-19, the levels of complement C3 correlated with disease severity and tended to be a good predictor of adverse outcome.