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Distinct Inflammatory Biomarker Patterns in COVID-19 Associated Multisystem Inflammatory Syndrome in Children (MIS-C) Suggest Overlap between Kawasaki Disease and Macrophage Activation Syndrome

31 Pages Posted: 22 Feb 2021

See all articles by Jackeline Rodriguez-Smith

Jackeline Rodriguez-Smith

University of Cincinnati - Department of Pediatrics

Emely L. Verweyen

Cincinnati Children's Hospital Medical Center - Division of Rheumatology

Gwendolyn M. Clay

Cincinnati Children's Hospital Medical Center - Division of Rheumatology

Ysabella M. Esteban

Cincinnati Children's Hospital Medical Center - Division of Rheumatology

Sarah R. de Loizaga

Cincinnati Children's Hospital Medical Center - Heart Institute

Elizabeth Joy Baker

Cincinnati Children's Hospital Medical Center - Division of Rheumatology

Thuy Do

Cincinnati Children's Hospital Medical Center - Division of Rheumatology

Sean M. Lang

Cincinnati Children's Hospital Medical Center - Heart Institute

Alexei A. Grom

Cincinnati Children's Hospital Medical Center - Division of Rheumatology

David Grier

Cincinnati Children's Hospital Medical Center - Division of Pathology and Laboratory Medicine

Grant S. Schulert

Cincinnati Children's Hospital Medical Center - Division of Rheumatology

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Abstract

Background: Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening hyperinflammatory syndrome that occurs after primary SARS-CoV-2 infection. The pathogenesis of MIS-C remains undefined, and whether specific inflammatory biomarker patterns can distinguish MIS-C from other hyperinflammatory syndromes including Kawasaki disease (KD) and macrophage activation syndrome (MAS) is unknown.

Methods: We studied a prospective cohort of nineteen MIS-C and nine KD patients and an established cohort of eleven new onset SJIA and nine MAS associated SJIA patients. Clinical and laboratory features as well as S100A8/A9, S100A12, IL-18, CXCL9 and IL-6 levels were compared between disease groups.

Findings: KD and MIS-C patients have similar S100 proteins and IL-18 profiles but are distinguished by significantly higher levels of the IFN-γ-induced chemokine CXCL9 in MIS-C. Stratifying MIS-C patients by CXCL9 levels revealed differential severity of clinical and laboratory presentation. MIS-C with high CXCL9 levels was associated with acute kidney injury, altered mental status, a higher frequency of shock (40 vs 90%), myocardial dysfunction (20 vs 50%), and more severe systemic inflammatory markers, cytopenia, and coagulopathy. The low CXCL9 MIS-C group in contrast resembled KD patients including the frequency of coronary involvement. We also found that elevated S100A8/A9, S100A12 and IL-18 were useful in distinguishing SJIA from KD with high sensitivity and specificity.

Interpretation: Our findings show MIS-C is distinguished from KD primarily by elevated CXCL9. The stratification of CXCL9 levels of MIS-C patients provides support for MAS pathophysiology in patients with severe MIS-C, suggesting new approaches for diagnosis and management.

Funding: This work was supported by an Academic Research Clinical (ARC) award to AG and GS from the Cincinnati Children’s Research Foundation. GS was supported by NIAMS/NIH K08-AR072075, AG by P30-AR070549, and JRS and GC by T32-AR069512. EV was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG/448863690).

Declaration of Interests: AG has served as a consultant and received research support from Novartis, Sobi, NovImmune and AB2Bio. GS consulting fees from Novartis and SOBI. All other authors report no disclosures.

Ethics Approval Statement: The study was approved by the Institutional Review Board (CCHMC IRB2018-2408).

Keywords: IFN-γ, CXCL9, IL-18, S100, multi-organ dysfunction, cytokine storm, cytokine, chemokine, systemic juvenile idiopathic arthritis (SJIA)

Suggested Citation

Rodriguez-Smith, Jackeline and Verweyen, Emely L. and Clay, Gwendolyn M. and Esteban, Ysabella M. and de Loizaga, Sarah R. and Baker, Elizabeth Joy and Do, Thuy and Lang, Sean M. and Grom, Alexei A. and Grier, David and Schulert, Grant S., Distinct Inflammatory Biomarker Patterns in COVID-19 Associated Multisystem Inflammatory Syndrome in Children (MIS-C) Suggest Overlap between Kawasaki Disease and Macrophage Activation Syndrome. Available at SSRN: https://ssrn.com/abstract=3790491 or http://dx.doi.org/10.2139/ssrn.3790491

Jackeline Rodriguez-Smith

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

Emely L. Verweyen

Cincinnati Children's Hospital Medical Center - Division of Rheumatology ( email )

Cincinnati, OH 45229
United States

Gwendolyn M. Clay

Cincinnati Children's Hospital Medical Center - Division of Rheumatology ( email )

Cincinnati, OH 45229
United States

Ysabella M. Esteban

Cincinnati Children's Hospital Medical Center - Division of Rheumatology ( email )

Cincinnati, OH 45229
United States

Sarah R. De Loizaga

Cincinnati Children's Hospital Medical Center - Heart Institute ( email )

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Elizabeth Joy Baker

Cincinnati Children's Hospital Medical Center - Division of Rheumatology ( email )

Cincinnati, OH 45229
United States

Thuy Do

Cincinnati Children's Hospital Medical Center - Division of Rheumatology

Cincinnati, OH 45229
United States

Sean M. Lang

Cincinnati Children's Hospital Medical Center - Heart Institute ( email )

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Alexei A. Grom

Cincinnati Children's Hospital Medical Center - Division of Rheumatology ( email )

Cincinnati, OH 45229
United States

David Grier

Cincinnati Children's Hospital Medical Center - Division of Pathology and Laboratory Medicine ( email )

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Grant S. Schulert (Contact Author)

Cincinnati Children's Hospital Medical Center - Division of Rheumatology ( email )

Cincinnati, OH 45229
United States

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