Commentary on “Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy” by D.C. Mastellos et al.

To the Editors,

We read with great interest the report by Mastellos and colleagues on the efficacy of complement-targeting drugs for abrogating various components of hyper-inflammation responses in cohorts of patients presenting with severe COVID-19 [1].

These findings obviously point to an important role for complement in the physiopathology of COVID-19. They also raise the hypothesis that complement is involved in the manifestation of delirium, a clinical symptom and a medical complication observed in typical severe cases of COVID-19 [2], but also in 80% of patients under treatment in intensive care units [3,4]. Confirmation of this hypothesis will justify examining if genotypes of complement components, especially C4, and the clinical symptom of delirium itself are useful as prognostic markers that can guide certain interventions for ICU patients presenting with severe COVID-19. The facts that support this hypothesis and the candidate biomarkers are as follows.

Both schizophrenia [5] and delirium [6], including the delirium of critically ill COVID-19 patients [7] have recently been shown to be heritable conditions. While changes in mental functions in psychiatric diseases such as schizophrenia do not, by definition, meet the criteria for delirium, psychotic symptoms are components of delirium. Indeed, Charlton and Kavanau [8] have proposed a model that integrates delirium and psychosis and that also places delirium as a spectrum of manifestations in psychiatric disease.

Importantly, through a meta-analysis of genome-wide association studies on schizophrenia, Sekar and colleagues found an association between phenotype, i.e., schizophrenia or health, and alleles of the complement component 4 (C4) genes [9]. Also importantly, these alleles generate levels of C4 expression in the brain that vary widely and are associated with phenotype. Furthermore, those authors also showed that C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. Of even further interest is the fact the genetic variants of C4 explain sex biases for many diseases in men [10], of which COVID-19 is probably the most recent and currently notorious example.

It is therefore reasonable to hypothesize that complement may participate in the generation of delirium that frequently occurs in critically ill patients, including severe COVID-19. Mastellos and colleagues did not address delirium in the report involving their cohorts and it would be interesting to make this observation in future clinical trials of the C5-targeting monoclonal antibody eculizumab and of the compstatin-based C3-targeted drug candidate AMY-101, both being components that are downstream from C4 in the complement cascade.