Cytokine Storms: Understanding COVID-19

Abstract

The elevated circulating levels of cytokines associated with a variety of infectious and immune-mediated conditions are frequently termed a cytokine storm. Here, we explain the protective functions of cytokines in "ideal" responses; the multi-factorial origins that can drive these responses to become pathological; and how this ultimately leads to vascular damage, immunopathology, and worsening clinical outcomes.

Figure 1

Kinetics of Cytokine Storms Cytokine storms have many different underlying causes that can manifest with different kinetics. (A) The solid line depicts the natural arc of an immune response to infection over a period of days to weeks that transitions to a resolution phase as a pathogen is controlled. For microorganisms with a high replicative potential, changes in the magnitude and duration of the immune response can result in systemic immune pathology. The two dotted lines illustrate different arcs associated with a cytokine storm through either an increased amplitude or a failure to enter the resolution phase. (B) The rapid and widespread engagement of adaptive responses by bacterially derived superantigens or therapeutic interventions can lead to a rapid surge in immune activity (hour-days) associated with supra-physiological levels of circulating cytokines. (C) Certain cancers that have a systemic component can lead to sustained (weeks to months) responses associated with elevated cytokine production. Likewise, chronic autoimmune diseases such as juvenile idiopathic arthritis (JIA) and lupus can have flares associated with increased cytokine production. There are also genetic defects closely linked to aberrant cytokine production, enhanced signaling, or a failure to fully control certain viral infections, which can cause periodic spikes in immune hyperactivity.

Figure 2

Pathophysiology of a Cytokine Storm An infectious or non-infectious stimulus in barrier sites such as the gut or lungs that leads to tissue damage initiates a complex series of events. In circumstances that leads to vascular damage, the coagulation system is critical for tissue repair, but this can progress to the development of DIC. The early response to microbial invasion or tissue damage is characterized by the innate production of cytokines and the induction of emergency granulopoiesis that leads to the mobilization of neutrophils and monocytes. These events will engage and amplify NK and T cell production of proinflammatory cytokines. These can promote capillary leak syndrome and thrombus formation that can progress to DIC. High circulating levels of these cytokines can cause cell death and tissue damage, while their ability to activate macrophages can lead to erythro-phagocytosis and anemia. The combination of anemia, alterations in vascular hemostasis, and cytokine-mediated damage can result in multi-organ failure.