Evidence, detailed characterization and clinical context of complement activation in acute multisystem inflammatory syndrome in children

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a rare, life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MIS-C develops with high fever, marked inflammation and shock-like picture several weeks after exposure to, or mild infection with SARS-CoV-2. Deep immune profiling identified activated macrophages, neutrophils, B-plasmablasts and CD8 + T cells as key determinants of pathogenesis together with multiple inflammatory markers. The disease rapidly responds to intravenous immunoglobulin (IVIG) treatment with clear changes of immune features. Here we present the results of a comprehensive analysis of the complement system in the context of MIS-C activity and describe characteristic changes during IVIG treatment. We show that activation markers of the classical, alternative and terminal pathways are highly elevated, that the activation is largely independent of anti-SARS-CoV-2 humoral immune response, but is strongly associated with markers of macrophage activation. Decrease of complement activation is closely associated with rapid improvement of MIS-C after IVIG treatment.

Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome

“…Previous adult studies have demonstrated elevation of C5a and soluble C5b-9 in patients with COVID-19, as well as deposition of activated complement proteins in injured tissues and organs . Previous reports determined that MIS-C and acute COVID-19 children were associated with highly elevated levels of activation markers of the classical, alternative, and terminal pathways . Children with SARS-CoV-2 infection exhibited elevated levels of soluble C5b9, which correlated with disease severity .…”

“…11,20 Previous reports determined that MIS-C and acute COVID-19 children were associated with highly elevated levels of activation markers of the classical, alternative, and terminal pathways. 21,22 Children with SARS-CoV-2 infection exhibited elevated levels of soluble C5b9, which correlated with disease severity. 13,[22][23][24][25] However, there remains a paucity of information on the degree and the possible involvement of complement in the pathogenesis of MIS-C and acute COVID-19 in children, especially from low middle-income countries.…”

Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups

“…Since C5b-9 levels were shown to correlate with disease severity in both cohorts ( 40 , 49 ), and all non-survivors except from one belonged to the severe COVID-19 group (SEV), the comparison was repeated with further stratifying according to the two severity groups. As seen in Supplementary Figure 6 , disease severity does indeed confound the analysis, since C5b-9 levels did not differ significantly anymore between severely infected survivors (alive) and non-survivors (deceased).…”

Hemolytic uremic syndrome in the setting of COVID-19 successfully treated with complement inhibition therapy: An instructive case report of a previously healthy toddler and review of literature

“…Even though the most common cause of TMA in children is infection with Shiga toxin producing E. coli (STEC), complement-mediated TMA should not be overlooked, especially considering novel triggers for development of hemolytic uremic syndrome (HUS), a common representative of complement-mediated TMA in children ( 5 – 8 ). Moreover, MIS-C, one of the more serious complications of COVID-19 in children likewise presents with features of TMA paired with complement activity dysregulation ( 2 , 9 , 10 ) ( Table 1 ). This denotes not only a possible diagnostic dilemma, considering the similarities of both HUS and MIS-C, especially when presenting with acute kidney injury (AKI), but also a challenge in timely selection of the most appropriate therapeutic modality.…”