Complement C5a and Clinical Markers as Predictors of COVID-19 Disease Severity and Mortality in a Multi-Ethnic Population

Abstract

Coronavirus disease-2019 (COVID-19) was declared as a pandemic by WHO in March 2020. SARS-CoV-2 causes a wide range of illness from asymptomatic to life-threatening. There is an essential need to identify biomarkers to predict disease severity and mortality during the earlier stages of the disease, aiding treatment and allocation of resources to improve survival. The aim of this study was to identify at the time of SARS-COV-2 infection patients at high risk of developing severe disease associated with low survival using blood parameters, including inflammation and coagulation mediators, vital signs, and pre-existing comorbidities. This cohort included 89 multi-ethnic COVID-19 patients recruited between July 14th and October 20th 2020 in Doha, Qatar. According to clinical severity, patients were grouped into severe (n=33), mild (n=33) and asymptomatic (n=23). Common routine tests such as complete blood count (CBC), glucose, electrolytes, liver and kidney function parameters and markers of inflammation, thrombosis and endothelial dysfunction including complement component split product C5a, Interleukin-6, ferritin and C-reactive protein were measured at the time COVID-19 infection was confirmed. Correlation tests suggest that C5a is a predictive marker of disease severity and mortality, in addition to 40 biological and physiological parameters that were found statistically significant between survivors and non-survivors. Survival analysis showed that high C5a levels, hypoalbuminemia, lymphopenia, elevated procalcitonin, neutrophilic leukocytosis, acute anemia along with increased acute kidney and hepatocellular injury markers were associated with a higher risk of death in COVID-19 patients. Altogether, we created a prognostic classification model, the CAL model (C5a, Albumin, and Lymphocyte count) to predict severity with significant accuracy. Stratification of patients using the CAL model could help in the identification of patients likely to develop severe symptoms in advance so that treatments can be targeted accordingly.

α2,6-Sialylation is Upregulated in Severe COVID-19 Implicating the Complement Cascade

“…Both C5 and C9 have been associated with severe COVID-19 and contribute to MAC-induced cell death and damage ( Fig. 5a ) 57, 58 . To gain insight into whether we are observing a change in sialylation or complement levels, we performed SNA pulldowns from pooled plasma samples from mild and severe COVID-19 patients and controls and performed Western blot analysis for C5 and C9 ( Fig.…”

Duration of COVID-19 mRNA Vaccine Effectiveness against Severe Disease

“…The presence of T follicular helper cells in germinal centers indicates active affinity maturation with diverse antibody production conferring enhanced protection [ 33 , 34 ]. Indeed, publications from our group [ 35 , 36 ] and several others have shown a direct correlation of decreased lymphocyte count with COVID-19 severity and mortality, while higher lymphocyte counts confer protection [ 37 , 38 , 39 ]. Interestingly, increased pro-inflammatory myeloid cells in the lung tissue and peripheral blood correlate with mortality and age [ 40 ].…”

“…The distribution of the individuals in the matched case-control study (stratified by case and control status) in relation to age, sex, time interval (in relation to vaccination), comorbidity category, and vaccine type is reported in Table 1. Among these study participants, median interval between the first and second dose was 21 days (IQR 21-28) for the BNT162b2 vaccine, and 28 days (IQR [28][29][30][31][32][33][34][35] for the mRNA-1273 vaccine. The median interval from the second to the third (booster) dose among the study participants was 239 days (IQR 210-264).…”

SARS-CoV-2 Induces Cytokine Responses in Human Basophils

“…An activated phenotype of basophils was also documented in COVID-19 patients ( 11 ) though the underlying mechanisms are not known. In view of activation of complement pathway in COVID-19 patients ( 28 – 30 ) and that human basophils express C5aR and C3aR ( 31 ), indirect activation of basophils in COVID-19 patients through complement components cannot be ruled out. However, direct or indirect interaction of basophils with SARS-CoV-2 has not been investigated yet, despite their vital role in the pulmonary pathologies and regulation of immune responses.…”