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New insights into the role of INF in “hyperinflammation”, endothelial injury,

and two different COVID outcomes

Transl Res 2021 Mar 5;S1931-5244(21)00052-9. COVID-19 and Cytokine Storm Syndrome: Are there lessons from Macrophage Activation Syndrome? Michael J Ombrello 1, Grant S Schulert 2 Affiliations

  • 1 Translational Genetics and Genomics Unit, Pediatric Translational Research Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, 10 Center Drive, 13C101A, MSC1560, Bethesda, Maryland 20852-1560, United States.

  • 2 Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, 10 Center Drive, 13C101A, MSC1560, Bethesda, Maryland 20852-1560, United States.

Abstract Although interest in “cytokine storms” has surged over the past decade, it was massively amplified in 2020 when it was suggested that a subset of patients with COVID-19 developed a form of cytokine storm. The concept of cytokine storm syndromes (CSS) encompasses diverse conditions or circumstances that coalesce around potentially lethal hyperinflammation with hemodynamic compromise and multiple organ dysfunction syndrome. Macrophage activation syndrome (MAS) is a prototypic form of CSS that develops in the context of rheumatic diseases, particularly systemic juvenile idiopathic arthritis. The treatment of MAS relies heavily upon corticosteroids and cytokine inhibitors, which have proven to be lifesaving therapies in MAS, as well as in other forms of CSS. Within months of the recognition of SARS-CoV2 as a human pathogen, descriptions of COVID-19 patients with hyperinflammation emerged. Physicians immediately grappled with identifying optimal therapeutic strategies for these patients, and despite clinical distinctions such as marked coagulopathy with endothelial injury associated with COVID-19, borrowed from the experiences with MAS and other CSS. Initial reports of patients treated with anti-cytokine agents in COVID-19 were promising, but recent large, better-controlled studies of these agents have had mixed results suggesting a more complex pathophysiology. Here, we discuss how the comparison of clinical features, immunologic parameters and therapeutic response data between MAS and hyperinflammation in COVID-19 can provide new insight into the pathophysiology of CSS. Copyright © 2021. Published by Elsevier Inc.

Figure 2 Timing and Strength of Type I IFN Responses in COVID-19. Clearance of SARS-CoV2 is uniquely dependent on type I IFN signaling. Most healthy individuals with COVID-19 are capable of activating type I IFN pathways, clearing the viral infection and normalizing the host environment with only mild symptoms. In the context of large viral loads or impaired IFN signaling pathways, dampened or inadequate IFN responses may lead to failure of antiviral responses and viral persistence. Persistent viral infection leads to chronic and pathologic elevation of type I IFN signaling which that propagates the pro-inflammatory amplification loop that is indicative of severe COVID-19. Adapted from Park A, Iwasaki A. Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host Microbe. 2020;27(6):870-878.


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