Are all cytokine storms the same?

Abstract

Cytokine release syndrome (CRS) is the result of massive pro-inflammatory cytokine release and imbalance in the absence of adequate immunomodulation from signals such as interleukin (IL)-10, resulting in ongoing inflammation, tissue damage and death if left uncontrolled. Although CRS can result from different pro-inflammatory insults, the treatments proposed are similar, regardless of the phase of response. SARS-CoV-2 causes COVID-19, and CRS has been a defining feature of severe disease. Common approaches to treating CRS in other conditions are now applied to COVID-19 and, although some patients respond, it begs the following questions: (1) are all cytokine storms the same regardless of initiating insult, (2) can treatments be considered equally for all CRS events at any phase of the response, (3) can CRS be predicted based on dynamic acute biomarkers and, (4) should patients with CRS undergo long-term monitoring for secondary effects? The aim of this commentary is not to provide a review of COVID-19 pathophysiology or of cytokine storm, but rather to establish a foundation which could act as a platform to inform treatment approaches to CRS, regardless of cause, and the short- and long-term follow-up which may be necessary for affected patients.

Keywords: COVID-19; CRS; Cytokine release syndrome; Cytokine storm; SARS-CoV-2; TGN1412.

Fig. 1

Dynamics of immune imbalance in CRS. A Key factors in CRS activation, exposure entry points and on- or off-target effects of the inciting agent. Other organs not included here can also be affected, e.g. heart, liver and kidneys. B Activation of cells in the target tissues initiate a cytokine cascade and activation of other cell types resulting in cell proliferation, further cytokine release and propagation of tissue damage. C Cytokine balance usually ensues following innate immune activation with the inciting agent. Cytokine imbalance with a massive release of pro-inflammatory cytokines initiates CRS, which is further propagated by prolonged and excessive IL-6 levels or inadequate IL-10 expression. D The temporal dynamics of CRS shows an initial innate immune response with an early release of pre-stored TNFα, followed immediately by IFN-γ, then IL-1β, and IL-6. IL-10 is released in response to the pro-inflammatory cytokines to immunomodulate early on, but an inadequate counter-balancing level (downward arrow), or prolonged IL-1β or IL-6 levels (horizontal arrows) will cause increasing CRS toxicities, including multi-organ failure, neurotoxicity and death. Bone marrow and T-cell responses are shown over a one year period. The T-cell peak is much earlier in the case of CAR-T-cell infusion. The dynamics of T-cell subsets is varied with CD4⁺RO⁺ or CD8⁺RO⁺ cells (dependent on the initiating agent, e.g. targeted antibody vs virus) stimulated primarily over the first months, followed by a transition to an increase in effector memory T-cells. Tregs cycle circannually at low levels throughout and in those who have γδTcell responses, an initial rise is followed by a gradual decline over years. Monocytes and DCs have different kinetic signatures, and RBCs follow the recovery trajectory of cDCs, possibly related to resolved hemophagocytosis following CRS. Dynamic treatment options, informed by the temporal stage of CRS and the immune imbalance which exists at the time, are shown, both in the immediate acute phase within the first 10 days, as well as in the follow-up phase during which immune- and organ-specific monitoring would inform treatment. Further potential cytokine release, at lower but more persistent levels, may occur in some patients concurrent with organ-specific symptoms (e.g. headache, gut irritability) following the release of CRS immunomodulation and recovery of immune cell subsets during the acute phase. CRS: Cytokine Release Syndrome; Mo: Monocyte; Mφ: Macrophage; DC: Dendritic Cell; ARDS: Acute Respiratory Distress Syndrome; RBC: Red Blood Cell; Plts: Platelets; EC: Endothelial Cell; TC: Tumor Cell; BC: B-Cell; Tc: T-cell; NKC: Natural Killer Cell; TNFα: Tumor Necrosis Factor alpha; IFNγ: Interferon gamma; IL: Interleukin; cDC: Classical Dendritic Cell; pDC: Plasmacytoid Dendritic Cell; FU: Follow-up; ANTI: Antibody against specified cytokine or cytokine receptor action; JAK1/2i: Janus Kinase 1 or 2 inhibitor; BTKi: Bruton Tyrosine Kinase inhibitor; mTORi: mammalian Target of Rapamycin inhibitor

Fig. 1

Dynamics of immune imbalance in CRS. A Key factors in CRS activation, exposure entry points and on- or off-target effects of the inciting agent. Other organs not included here can also be affected, e.g. heart, liver and kidneys. B Activation of cells in the target tissues initiate a cytokine cascade and activation of other cell types resulting in cell proliferation, further cytokine release and propagation of tissue damage. C Cytokine balance usually ensues following innate immune activation with the inciting agent. Cytokine imbalance with a massive release of pro-inflammatory cytokines initiates CRS, which is further propagated by prolonged and excessive IL-6 levels or inadequate IL-10 expression. D The temporal dynamics of CRS shows an initial innate immune response with an early release of pre-stored TNFα, followed immediately by IFN-γ, then IL-1β, and IL-6. IL-10 is released in response to the pro-inflammatory cytokines to immunomodulate early on, but an inadequate counter-balancing level (downward arrow), or prolonged IL-1β or IL-6 levels (horizontal arrows) will cause increasing CRS toxicities, including multi-organ failure, neurotoxicity and death. Bone marrow and T-cell responses are shown over a one year period. The T-cell peak is much earlier in the case of CAR-T-cell infusion. The dynamics of T-cell subsets is varied with CD4⁺RO⁺ or CD8⁺RO⁺ cells (dependent on the initiating agent, e.g. targeted antibody vs virus) stimulated primarily over the first months, followed by a transition to an increase in effector memory T-cells. Tregs cycle circannually at low levels throughout and in those who have γδTcell responses, an initial rise is followed by a gradual decline over years. Monocytes and DCs have different kinetic signatures, and RBCs follow the recovery trajectory of cDCs, possibly related to resolved hemophagocytosis following CRS. Dynamic treatment options, informed by the temporal stage of CRS and the immune imbalance which exists at the time, are shown, both in the immediate acute phase within the first 10 days, as well as in the follow-up phase during which immune- and organ-specific monitoring would inform treatment. Further potential cytokine release, at lower but more persistent levels, may occur in some patients concurrent with organ-specific symptoms (e.g. headache, gut irritability) following the release of CRS immunomodulation and recovery of immune cell subsets during the acute phase. CRS: Cytokine Release Syndrome; Mo: Monocyte; Mφ: Macrophage; DC: Dendritic Cell; ARDS: Acute Respiratory Distress Syndrome; RBC: Red Blood Cell; Plts: Platelets; EC: Endothelial Cell; TC: Tumor Cell; BC: B-Cell; Tc: T-cell; NKC: Natural Killer Cell; TNFα: Tumor Necrosis Factor alpha; IFNγ: Interferon gamma; IL: Interleukin; cDC: Classical Dendritic Cell; pDC: Plasmacytoid Dendritic Cell; FU: Follow-up; ANTI: Antibody against specified cytokine or cytokine receptor action; JAK1/2i: Janus Kinase 1 or 2 inhibitor; BTKi: Bruton Tyrosine Kinase inhibitor; mTORi: mammalian Target of Rapamycin inhibitor