Gert van der Hoek
In Memoriam - Editor, Senior Moderator
December 3, 2020
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has reminded us of the critical role of an effective host immune response and the devastating effect of immune dysregulation. This year marks 10 years since the first description of a cytokine storm that developed after chimeric antigen receptor (CAR) T-cell therapy[SUP]1[/SUP] and 27 years since the term was first used in the literature to describe the engraftment syndrome of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation.[SUP]2[/SUP] The term “cytokine release syndrome” was coined to describe a similar syndrome after infusion of muromonab-CD3 (OKT3).[SUP]3[/SUP] Cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders.
From a historical perspective, cytokine storm was previously referred to as an influenza-like syndrome that occurred after systemic infections such as sepsis and after immunotherapies such as Coley’s toxins.[SUP]4[/SUP]Yersinia pestis infection (i.e., the plague) has led to major pandemics (e.g., the Black Death) and triggers alveolar macrophages to produce excessive amounts of cytokines, resulting in cytokine storm.[SUP]5[/SUP] An exaggerated immune response was suspected to contribute to the lethality of the 1918–1919 influenza pandemic. In fact, a reconstructed H1N1 virus isolated from the 1918 pandemic, as compared with common reference strains of the virus that causes influenza A, triggered marked pulmonary inflammation in mice.[SUP]6[/SUP] Recognition that the immune response to the pathogen, but not the pathogen itself, can contribute to multiorgan dysfunction and that similar cytokine storm syndromes could occur with no obvious infection led to the investigation of immunomodulators and cytokine-directed therapies. One of the earliest targeted therapies for abrogation of a cytokine storm was the anti–interleukin-6 receptor monoclonal antibody tocilizumab, which was developed for the treatment of idiopathic multicentric Castleman’s disease in the 1990s. A host of other disorders have been described as causes of cytokine storm and targeted with immune-directed therapies, such as sepsis, primary and secondary hemophagocytic lymphohistiocytosis (HLH), autoinflammatory disorders, and coronavirus disease 2019 (Covid-19).
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Summary
Mild, secondary organ dysfunction during an inflammatory response is evolutionarily acceptable if it allows the host to overcome the infection and survive. If the inflammatory response causes excessive organ dysfunction that puts host survival and reproductive fitness at risk (in the absence of ventilatory support and dialysis), then it is pathologic. Extensive regulatory mechanisms exist that modulate the immune response and prevent cytokine storm. Nevertheless, the disorder can still occur due to iatrogenic causes, pathogens, cancers, autoimmunity, and autoinflammatory mechanisms.
Distinguishing between protective inflammatory responses and pathologic cytokine storm has important implications for treatment and is quite challenging. No unifying definition of cytokine storm exists, and there is much disagreement about what the definition should be and whether specific conditions such as Covid-19 should be included in the spectrum of cytokine storm disorders. We propose a unifying definition for cytokine storm that is based on the following criteria: elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction beyond that which could be attributed to a normal response to a pathogen, if a pathogen is present.
Targeted therapeutic approaches to cytokine storm associated with idiopathic multicentric Castleman’s disease, HLH, or CAR T-cell therapy have turned deadly conditions into often reversible states. Given advances in “multi-omic” profiling and therapeutic modulation of the immune system, as well as concerted efforts to work across the cytokine storm umbrella, we expect to see continued improvements in outcomes.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has reminded us of the critical role of an effective host immune response and the devastating effect of immune dysregulation. This year marks 10 years since the first description of a cytokine storm that developed after chimeric antigen receptor (CAR) T-cell therapy[SUP]1[/SUP] and 27 years since the term was first used in the literature to describe the engraftment syndrome of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation.[SUP]2[/SUP] The term “cytokine release syndrome” was coined to describe a similar syndrome after infusion of muromonab-CD3 (OKT3).[SUP]3[/SUP] Cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders.
From a historical perspective, cytokine storm was previously referred to as an influenza-like syndrome that occurred after systemic infections such as sepsis and after immunotherapies such as Coley’s toxins.[SUP]4[/SUP]Yersinia pestis infection (i.e., the plague) has led to major pandemics (e.g., the Black Death) and triggers alveolar macrophages to produce excessive amounts of cytokines, resulting in cytokine storm.[SUP]5[/SUP] An exaggerated immune response was suspected to contribute to the lethality of the 1918–1919 influenza pandemic. In fact, a reconstructed H1N1 virus isolated from the 1918 pandemic, as compared with common reference strains of the virus that causes influenza A, triggered marked pulmonary inflammation in mice.[SUP]6[/SUP] Recognition that the immune response to the pathogen, but not the pathogen itself, can contribute to multiorgan dysfunction and that similar cytokine storm syndromes could occur with no obvious infection led to the investigation of immunomodulators and cytokine-directed therapies. One of the earliest targeted therapies for abrogation of a cytokine storm was the anti–interleukin-6 receptor monoclonal antibody tocilizumab, which was developed for the treatment of idiopathic multicentric Castleman’s disease in the 1990s. A host of other disorders have been described as causes of cytokine storm and targeted with immune-directed therapies, such as sepsis, primary and secondary hemophagocytic lymphohistiocytosis (HLH), autoinflammatory disorders, and coronavirus disease 2019 (Covid-19).
..................................................................................
Summary
Mild, secondary organ dysfunction during an inflammatory response is evolutionarily acceptable if it allows the host to overcome the infection and survive. If the inflammatory response causes excessive organ dysfunction that puts host survival and reproductive fitness at risk (in the absence of ventilatory support and dialysis), then it is pathologic. Extensive regulatory mechanisms exist that modulate the immune response and prevent cytokine storm. Nevertheless, the disorder can still occur due to iatrogenic causes, pathogens, cancers, autoimmunity, and autoinflammatory mechanisms.
Distinguishing between protective inflammatory responses and pathologic cytokine storm has important implications for treatment and is quite challenging. No unifying definition of cytokine storm exists, and there is much disagreement about what the definition should be and whether specific conditions such as Covid-19 should be included in the spectrum of cytokine storm disorders. We propose a unifying definition for cytokine storm that is based on the following criteria: elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction beyond that which could be attributed to a normal response to a pathogen, if a pathogen is present.
Targeted therapeutic approaches to cytokine storm associated with idiopathic multicentric Castleman’s disease, HLH, or CAR T-cell therapy have turned deadly conditions into often reversible states. Given advances in “multi-omic” profiling and therapeutic modulation of the immune system, as well as concerted efforts to work across the cytokine storm umbrella, we expect to see continued improvements in outcomes.
