By Liriye Kurtovic and James G. Beeson

SARS-CoV-2 infection can lead to mild respiratory illness and in some patients, acute respiratory distress syndrome (ARDS), often associated with increased inflammation. One inflammatory mediator that has been in the spotlight recently is the complement system. Complement activity has been reportedly elevated in COVID-19 patients and therefore associated with disease pathology. However, in contrast to this role, complement is known to contribute to immunity against many viral and other pathogens and may also play a protective role against SARS-CoV-2, which is currently unknown. Before ruling that complement is guilty of causing disease, we sought out to review the evidence of complement activation during COVID-19.

Complement is central to the immune system, acting as an innate and adaptive response to infection. We reviewed available clinical studies and found that while serum concentrations of activate complement proteins were elevated in COVID-19 patients, the significance of this was often not clear as levels were often within the normal healthy range. Furthermore, complement activity was considerably lower than observed in other inflammatory syndromes, such as bacterial sepsis. Complement has been shown to enhance antibody-mediated virus neutralization (E.g. West Nile virus), and lead to lysis of the virus (E.g. Zika virus) and virus-infected cells (E.g. influenza virus). Disappointingly, there has been little investigation into the potential role of antibody-complement interactions against SARS-CoV-2. This may be due to the assumption that complement activation is hyper-inflammatory and contributes to disease pathology, but the evidence to support this is limited. On this note, most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) in development are human IgG1, which has the structural properties to activate complement. Yet, there is no evidence of these mAbs excessively activating complement in clinical trials. We can therefore speculate that antibody-complement interactions are not hyper-inflammatory, although, this needs to be formally evaluated.

Figure: Potential Mechanisms of Innate and Adaptive Complement Activation against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

There has been interest in the use of complement inhibitors to treat COVID-19. Thus far, only few case reports or case series have been published, which report both positive and negative clinical outcomes for patients receiving complement inhibitors in addition to other therapies. In the one controlled trial performed, complement inhibitor treatment did not significantly improve the primary outcome of respiratory function.

Altogether, complement activity may be elevated in COVID-19 patients and control contribute to disease pathology in some individuals. However, more evidence is needed to support this conclusion. There is currently little known on the potential protective roles of complement, and limited evidence that complement inhibitor therapies have a significant benefit to COVID-19 patients. Until further evidence is available, we rule complement as “not guilty”. Furthermore, complement may have protective roles that need to be investigated.

See the full article here:  https://www.cell.com/trends/immunology/fulltext/S1471-4906(20)30283-0

Table summarizing studies of serum complement concentrations in COVID-19 patients versus controls

https://www.cell.com/action/showFullTableHTML?isHtml=true&tableId=t0005&pii=S1471-4906%2820%2930283-0

References

Kurtovic, L. and Beeson, J.G. (2020) Complement factors in COVID-19 therapeutics and vaccines. Trends in Immunology. 42 (2), 94-103.

Mehlhop, E. et al. (2009) Complement protein C1q reduces the stoichiometric threshold for antibody-mediated neutralization of West Nile virus. Cell Host & Microbe 6 (4), 381-391.

Du, H. et al. (2020) Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status. Allergy, 2020;00:1–23.

Vlaar, A.P. et al. (2020) Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. The Lancet Rheumatology 2 (12), E764-E773.