Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease

Background Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C. Therefore, we explored the immunological response, presence of ACAAs and disease correlates in both disorders. Methods Eighteen inflammatory plasma protein levels and seven ACAAs were measured in KD (n = 216) and MIS-C (n = 56) longitudinally by Luminex and/or ELISA. Levels (up to 1 year post-onset) of these proteins were related to clinical data and compared with healthy paediatric controls. Findings ACAAs were found in both patient groups. The presence of ACAAs lagged behind the inflammatory plasma proteins and peaked in the subacute phase. ACAAs were mostly directed against IFN-& gamma; (>80%) and were partially neutralising at best. KD presented with a higher variety of ACAAs than MIS-C. Increased levels of anti-IL-17A (P = 0.02) and anti-IL-22 (P = 0.01) were inversely associated with ICU admission in MIS-C. Except for CXCL10 in MIS-C (P = 0.002), inflammatory plasma proteins were elevated in both KD and MIS-C. Endothelial angiopoietin-2 levels were associated with coronary artery aneurysms in KD (P = 0.02); and sCD25 (P = 0.009), angiopoietin-2 (P = 0.001), soluble IL-33-receptor (ST2, P = 0.01) and CXCL10 (P = 0.02) with ICU admission in MIS-C. Interpretation Markers of endothelial activation (E-selectin, angiopoietin-2), and innate and adaptive immune responses (macrophages [CD163, G-CSF], neutrophils [lipocalin-2], and T cells [IFN-& gamma;, CXCL10, IL-6, IL-17]), are upregulated in KD and MIS-C. ACAAs were detected in both diseases and, although only partly neutralising, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation.

Automated summary

Compared with KD, MIS-C in children with SARS-CoV-2 has similar clinical features, and both diseases have been found to have anti-cytokine autoantibodies (ACAAs), especially antibodies against IFN-γ. In addition, in MIS-C, levels of anti-IL-17A and anti-IL-22 are negatively correlated with ICU admission. The study results indicate that markers of endothelial activation (E-selectin, angiopoietin-2), as well as innate and adaptive immune responses, are upregulated in both KD and MIS-C. ACAAs are present in both diseases and, although only partially neutralizing, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation.