CYTOKINE STORM VS CYTOKINE RELEASE SYNDROME

Cytokine storm syndrome is diverse set of conditions that can result in cytokine storm. Cytokine storm
syndromes include familiar hemophagocytic lymphohistiocytosis, Epstein-Barr virus–associated
hemophagocytic lymphohistiocytosis, systemic or non-systemic juvenile idiopathic arthritis–associated
macrophage activation syndrome, NLRC4 macrophage activation syndrome, cytokine release syndrome
and sepsis.[5]

Cytokine storms versus cytokine release syndrome[edit]

The term "cytokine storm" is often loosely used interchangeably with cytokine release syndrome (CRS)
but is more precisely a differentiable syndrome that may represent a severe episode of cytokine release
syndrome or a component of another disease entity, such as macrophage activation syndrome. When
occurring as a result of a therapy, CRS symptoms may be delayed until days or weeks after treatment.
Immediate-onset (fulminant) CRS appears to be a cytokine storm.[6]

History[edit]
The first reference to the term cytokine storm in the published medical literature appears to be by
Ferrara et al. in 1993 in a discussion of graft vs. host disease; a condition in which the role of excessive
and self-perpetuating cytokine release had already been under discussion for many years.[11][12] The
term next appeared in a discussion of pancreatitis in 2002, and in 2003 it was first used in reference to a
reaction to an infection.[11]

It is believed that cytokine storms were responsible for the disproportionate number of healthy young
adult deaths during the 1918 influenza pandemic, which killed 17 to 50 million people. In this case, a
healthy immune system may have been a liability rather than an asset.[13] Preliminary research results
from Taiwan also indicated this as the probable reason for many deaths during the SARS epidemic in
2003.[14] Human deaths from the bird flu H5N1 usually involve cytokine storms as well.[15] Cytokine
storm has also been implicated in hantavirus pulmonary syndrome.[16]

In 2006, a study at Northwick Park Hospital in England resulted in all 6 of the volunteers given the drug
theralizumab becoming critically ill, with multiple organ failure, high fever, and a systemic inflammatory
response.[17] Parexel, a company conducting trials for pharmaceutical companies, in one of its
documents, wrote about the trial and said theralizumab could cause a cytokine storm—the dangerous
reaction the men experienced.[18]

During the COVID-19 pandemic, some doctors attributed many deaths to cytokine storms.[19][20]

CRS
Cause[edit]
CRS occurs when large numbers of white blood cells, including B cells, T cells, natural killer cells,
macrophages, dendritic cells, and monocytes are activated and release inflammatory cytokines, which
activate more white blood cells in a positive feedback loop of pathogenic inflammation.[5] Immune cells
are activated by stressed or infected cells through receptor-ligand interactions.[9]

This can occur when the immune system is fighting pathogens, as cytokines produced by immune cells
recruit more effector immune cells such as T-cells and inflammatory monocytes (which differentiate into
macrophages) to the site of inflammation or infection. In addition, pro-inflammatory cytokines binding
their cognate receptor on immune cells results in activation and stimulation of further cytokine
production.[10] This process, when dysregulated, can be life-threatening due to systemic hyper-
inflammation, hypotensive shock, and multi-organ failure.[citation needed]

Adoptive cell transfer of autologous T-cells modified with chimeric antigen receptors (CAR-T cell
therapy) also causes CRS.[5] Serum samples of patients with CAR-T associated CRS have elevated levels
of IL-6, IFN-γ, IL-8 (CXCL8), IL-10, GM-CSF, MIP-1α/β, MCP-1 (CCL2), CXCL9, and CXCL10 (IP-10).[11] The
most predictive biomarkers 36h after CAR-T infusion of CRS are a fever ≥38.9°C (102°F) and elevated
levels of MCP-1 in serum.[12] Many of the cytokines elevated in CRS are not produced by CAR-T cells,
but by myeloid cells that are pathogenically licensed through T-cell-mediated activating mechanisms.
For example, in vitro co-culture experiments have demonstrated IL-6, MCP-1, and MIP-1 are not
produced by CAR-T cells, but rather by inflammatory myeloid lineage cells.[13] In vivo models have
demonstrated NSG (NOD/SCID/γ-chain deficient mice) with defects of both lymphocyte and myeloid
lineage compartments do not develop CRS after CAR-T cell infusion.[14]

In addition to adoptive T-cell therapies, severe CRS or cytokine reactions can occur in a number of
infectious and non-infectious diseases including graft-versus-host disease (GVHD), coronavirus disease
2019 (COVID-19), acute respiratory distress syndrome (ARDS), sepsis, Ebola, avian influenza, smallpox,
and systemic inflammatory response syndrome (SIRS).[15]

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sufficiently cleared by the
early acute phase anti-viral response in most individuals, some progress to a hyperinflammatory
condition, often with life-threatening pulmonary involvement. This systemic hyperinflammation results
in inflammatory lymphocytic and monocytic infiltration of the lung and the heart, causing ARDS and
cardiac failure.[16] Patients with fulminant COVID-19 and ARDS have classical serum biomarkers of CRS
including elevated CRP, LDH, IL-6, and ferritin.[17]

Hemophagocytic lymphohistiocytosis and Epstein-Barr virus-related hemophagocytic

lymphohistiocytosis are caused by extreme elevations in cytokines and can be regarded as one form of
severe cytokine release syndrome.[18]

Medications[edit]
Cytokine reaction syndrome may also be induced by certain medications, such as the CD20 antibody
rituximab and the CD19 CAR T cell tisagenlecleucel. The experimental drug TGN1412—also known as
Theralizumab—caused extremely serious symptoms when given to six participants in a Phase I trial.[2] A
controlled and limited CRS is triggered by active fever therapy with mixed bacterial vaccines (MBV)
according to Coley; it is used for oncological and certain chronic diseases.[19] CRS has also arisen with
biotherapeutics intended to suppress or activate the immune system through receptors on white blood
cells. Muromonab-CD3, an anti-CD3 monoclonal antibody intended to suppress the immune system to
prevent rejection of organ transplants; alemtuzumab, which is anti-CD52 and used to treat blood
cancers as well as multiple sclerosis and in organ transplants; and rituximab, which is anti-CD20 and
used to treat blood cancers and