Complement system component dysregulation is a distinctive feature of COVID-19 disease: a prospective and comparative analysis of patients admitted to the emergency department for suspected COVID-19 disease

Abstract

The complement system (CS) plays a pivotal role in Coronavirus disease 2019 (COVID-19) pathophysiology. The objective of this study was to provide a comparative, prospective data analysis of CS components in an all-comers cohort and COVID-19 patients. Patients with suspected COVID-19 infection admitted to the Emergency department were grouped for definite diagnosis of COVID-19 and no COVID-19 accordingly. Clinical presentation, routine laboratory and von Willebrand factor (vWF) antigen as well as CS components 3, 4 and activated 5 (C5a) were assessed. Also, total complement activity via the classical pathway (CH50) was determined. Levels of calprotectin in serum were measured using an automated quantitative lateral flow assay. We included 80 patients in this prospective trial. Of those 19 (23.7%) were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with COVID-19 had higher levels of CS components 5a and 4 (54.79 [24.14–88.79] ng/ml vs. 35 [23.15–46.1] ng/ml; p = 0.0433 and 0.3772 [± 0.1056] g/L vs. 0.286 [0.2375–0.3748] g/L; p = 0.0168). COVID-19 patients had significantly higher levels of vWF antigen when compared to the control group (288.3 [± 80.26] % vs. 212 [151–320] %; p = 0.0469). There was a significant correlation between CS C3 and 5a with vWF antigen (rs = 0.5957 [p = 0.0131] and rs = 0.5015 [p = 0.042]) in COVID-19 patients. There was no difference in calprotectin plasma levels (4.786 [± 2.397] µg/ml vs. 4.233 [± 2.142] µg/ml; p = 0.4175) between both groups. This prospective data from a single centre all-comers cohort accentuates altered levels of CS components as a distinct feature of COVID-19 disease. Deregulation of CS component 3 and C5a are associated with increased vWF antigen possibly linking vascular damage to alternative CS activation in COVID-19.

C5a elevation in convalescents from severe COVID-19 is not associated with early complement activation markers C3bBbP or C4d

“…Previously, we determined C5a levels in longitudinally collected serum samples from 49 patients suffering from C-19 with different clinical intensities and concluded that serum C5a levels remain high in severe cases of COVID-19 and are associated with the persistence of respiratory symptoms after hospital discharge ( 4 ). An increase in C5a proportional to the severity of the disease has been also reported in other studies using either plasma ( 1 , 2 , 6 ) or serum ( 3 – 5 ). The observation that C5a, normally cleared rapidly from the circulation ( 7 , 8 ), remains elevated in follow-up samples from COVID-19 convalescents made us investigate the source of this anaphylatoxin after the clearance of infection.…”

“…4). An increase in C5a proportional to the severity of the disease has been also reported in other studies using either plasma (1,2,6) or serum (3)(4)(5). The observation that C5a, normally cleared rapidly from the circulation (7,8), remains elevated in follow-up samples from COVID-19 convalescents made us investigate the source of this anaphylatoxin after the clearance of infection.…”

“…One of the hypotheses behind elevated C5a during the C-19 course involves the pro-coagulant state in the microvasculature of the lungs and kidneys ( 19 ). Notably, a strong correlation between C5a and von Willebrand factor was observed in C-19 patients ( 3 ). Regarding the cross talk of complement and the coagulation system, an important observation was made by Huber-Lang et al.…”

“…The elevated levels of complement C5a anaphylatoxin in the inflammatory response to COVID-19 (C-19) has been independently described by numerous research groups. A high concentration of C5a was associated with disease severity and predicted the outcome of hospitalized patients (1)(2)(3)(4)(5)(6). Our recent study showed that C5a was not only correlated with a clinical risk score and the severity of the disease but its high level persisted up to 90 days after hospital discharge in patients experiencing either a harsh course of C-19 or long-term respiratory symptoms (4).…”

Serum Proteome Signatures of Anti-SARS-CoV-2 Vaccinated Healthcare Workers in Greece Associated with Their Prior Infection Status

“…Our results further showed that the complement components C4b-binding protein and its alpha chain [P04003], as well as C9 [P02748] were elevated in the post-COVID-19 patient group compared to the uninfected. Consistent evidence was provided by a study reporting C4 elevation in patients with possible SARS-CoV-2 infection held in the Emergency Department [ 17 ]. Similarly, another study on patients with severe COVID-19 found elevated deposits of C5a to C9 in biopsies of skin and lung tissue [ 18 ].…”