COVID-19 and cytokine storm syndrome: are there lessons from macrophage activation syndrome?

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.

Fig 1

Comparison of macrophage activation syndrome and COVID-cytokine storm syndrome. Typical antiviral responses (left panel) produce expansion of virus-specific cytotoxic T lymphocytes (CTL), which interact with antigen presenting cells (APC) and macrophages to limit and eliminate the infection. After clearing the infection, the expanded population of activated immune cells are eliminated by cytolytic cells and the immune system returns to its typical basal level of surveillance. In macrophage activation syndrome (MAS; middle panel), innate immune activation and IL-18 drive the expansion of CTLs, their engagement with APCs and their cross-talk with macrophages. The combined persistence of innate immune activation and an inadequate cytolytic capacity to eliminate activated immune cells leads to prolonged CTL-APC engagement and continued production of inflammatory mediators, amplified CTL-macrophage cross-talk, and the cytokine storm of MAS. In COVID-19 (right panel), infection with SARS-CoV-2 stimulates these same anti-viral immune pathways with CTL expansion. Dampened type I interferon responses allow prolonged persistence of infection of the lungs and activation of type II interferon responses contribute to persistent immune activation. Failure to clear the virus lead to prolonged type I interferon signaling, driving proinflammatory cytokine production. As was the case in MAS, it is possible that inadequate cytolytic capacity due to immune exhaustion and/or defective anti-viral responses leads to prolonged cross-talk between CTL, APCs and alveolar macrophages, contributing to COVID-CS. Beyond the proinflammatory mechanisms implicated in other cytokine storm syndromes, activation of the complement cascade has been observed in severe COVID-19 patients and its specific contribution to pathophysiology are not yet known.

Fig 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 proinflammatory 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;27:870-878.