Complement C3 identified as a unique risk factor for disease severity among young COVID-19 patients in Wuhan, China

Abstract

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 possible non-linear influences remain unknown. Data were analyzed from COVID-19 patients with clinical outcome in a single hospital in Wuhan, China, collected retrospectively from Jan 24th to Mar 27th. 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 the clinical characteristics of a severe disease course. A total of 762 young patients (median age 47 years, interquartile range [IQR] 38–55, range 18–60; 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 statistically 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 serum amyloid A (SAA), C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased lymphocyte counts influence disease severity independently 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 of developing severe COVID-19 specifically in young patients, whereas 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. This study identified increased levels of complement C3 as a unique risk factor for adverse outcomes specific to young COVID-19 patients.

Complement activation predicts negative outcomes in COVID-19: The experience from Northen Italian patients.

“…Besides the high circulating levels of pro-inflammatory cytokines (e.g. Interleukin [IL]-6) there is growing evidence that complement activation plays a crucial role [ 6 ] as suggested by increased plasma levels of activation products (soluble C5b9 [sC5b-9], C5a) and complement deposits in the affected tissues of COVID-19 patients [ [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] ]. This finding is consistent with the complement involvement reported in several viral diseases including infections with other coronaviruses [ [27] , [28] , [29] ] and the suggested protective effects of complement blockade on COVID-19 [ 6 ].…”

In Silico Prediction of Hub Genes Involved in Diabetic Kidney and COVID-19 Related Disease by Differential Gene Expression and Interactome Analysis

“…This inter-relation could be feasible to contribute to the worsening of diabetic patients with DKD infected with the SARS-CoV-2 virus. This phenomenon has been reflected in ICU rooms, giving worse results in days of hospitalization or survival of those patients [ 44 , 45 , 46 ].…”

Discovering hub genes involved in the pathophysiological impact of COVID-19 on diabetes kidney disease by differential gene expression and interactome analysis

“…This inter-relation could be feasible to contribute to the worsening of diabetic patients with DKD infected with the SARS-CoV-2 virus. This phenomenon has been reflected in ICU rooms, giving worse results in days of hospitalization or survival of those types of patients [61-63]. Moreover, diabetic patients have also been reported to present a decrease in the fibrinolytic process [60], which further increases the risk of coagulation with COVID-19.…”

“…For instance, the mechanisms described in w the proteases of the coagulation cascade activate the complement pathways [59,60], and in turn, how the produc the activation of the complement pathways could activate platelets and the coagulation system. This inter-rela could be feasible to contribute to the worsening of diabetic patients with DKD infected with the SARS-CoV-2 v This phenomenon has been reflected in ICU rooms, giving worse results in days of hospitalization or survival of t types of patients [61][62][63]. Moreover, diabetic patients have also been reported to present a decrease in the fibrino process [60], which further increases the risk of coagulation with COVID-19.…”