In the setting of viral infections, additional effects mediated by the activation of the complement system include virus aggregation-mediated neutralization, phagocytosis, and lysis of viruses and virus-infected cells ( 3). This, in turn, initiates a sequence of events that include phagocytosis, leucocyte attraction and activation, mast cell and basophil degranulation with the release of several mediators of inflammation, activation of the inflammasome complex and specific cytokines, and B lymphocyte activation with the consequent secretion of specific antibodies ( 2). The activation of the classical, lectin, and alternative pathways ultimately leads to the cleavage of the central component 3, C3, by convertases. The complement system exerts several protective effects against infectious agents following activation during innate, through the alternative and lectin pathways, and acquired, through the classical pathway, immunity ( 1).
#C3 OR C4 MIDDLE C REGISTRATION#
Systematic Review Registration: PROSPERO, Registration number: CRD42021239634. C3 and C4 might be useful to predict adverse clinical consequences in these patients. In conclusion, lower concentrations of C3 and C4, indicating complement activation, were significantly associated with higher COVID-19 severity and mortality.
In meta-regression, the SMD of C3 was significantly associated with white blood cell count, C-reactive protein (CRP), and pro-thrombin time, whereas the SMD of C4 was significantly associated with CRP, pro-thrombin time, D-dimer, and albumin. Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not modified. Extreme between-study heterogeneity was observed (C3, I 2 = 82.1% C4, I 2 = 84.4%).
Both C3 and C4 concentrations were significantly lower in patients with high disease severity or non-survivor status than patients with low severity or survivor status (C3 SMD=-0.40, 95% CI -0.60 to -0.21, p<0.001 C4 SMD=-0.29, 95% CI -0.49 to -0.09, p=0.005 moderate certainty of evidence). Nineteen studies in 3,764 COVID-19 patients were included in the meta-analysis. Certainty of evidence was assessed using GRADE. Risk of bias was assessed using the Newcastle-Ottawa scale whereas publication bias was assessed with the Begg’s and Egger’s tests. Using a random-effects model, standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated to evaluate differences in serum C3 and C4 concentrations between COVID-19 patients with low vs. Eligibility criteria were a) reporting continuous data on serum C3 and C4 concentrations in COVID-19 patients, -b) investigating COVID-19 patients with different disease severity and/or survival status, c) adult patients, d) English language, e) ≥10 patients, and f) full-text available. We searched PubMed, Web of Science and Scopus, between January 2020 and February 2021, for studies reporting serum complement C3 and C4, measures of COVID-19 severity, and survival. We conducted a systematic review and meta-analysis with meta-regression to investigate possible differences in the serum concentrations of two routinely measured complement components, C3 and C4, in COVID-19 patients with different severity and survival status. 3Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, SA, AustraliaĪctivation of the complement system has been observed in coronavirus disease 19 (COVID-19).2Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.1Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
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