An immediate complication occurring with the use of anti-T cell antibody infusions such as ATG, OKT3 and TGN1412, but also with the CD-20 antibody rituximab, and Blinatumomab.
Neutrophils can produce neutrophil extracellular traps, which are a network of fibers that contribute to thrombi formation and amplify cytokine production during the cytokine storm.
Cytokine release syndrome is it complex process involving interconnected networks of cell types, signaling pathways, and cytokines including interferon-gamma, interleukin-1, interleukin-6, TNF, and interleukin-18 which are cytokines that often have elevated levels and are thought to have a central immuno pathologic role.
Severe cases of cytokine releasing syndrome are known as cytokine storms.
A pattern of cytokine elevations resulted on the basis of the microbiome, genetic features, and underlying disorders.
Interferon-gamma is primarily secreted by activated T cells and NK cells and activates macrophages.
When activated macrophages can secrete excessive amounts of cytokines, ultimately causing severe tissue damage that can lead to organ failure.
Hematophagocytic macrophages are often observed in bone marrow biopsy specimens from patients with cytokines storm.
Interferon gamma can induce hemophagocytosis by macrophages and contribute to cytopenias seen in patients with cytokine storm.
NK cells have a decreased function in some cases of cytokine storm and can lead to profound to prolonged antigenic stimulation and difficulty resolving inflammation.
Excess interleukin-6 may mediate the impairment in NK cell function.
The combination of renal dysfunction, endothelial cell death and acute phase hypoalbuminemia can lead to capillary leak syndrome and anasarca.
The process occurs as antibodies bind to the T cell receptor, activating the T cells before they are destroyed.
Th1 exaggerated inflammatory response occurs during cytokines storm.
Th1 cells produce large quantities of interferon gamma, induce delayed hypersensitivity reactions, activate macrophages and are essential for defense against intracellular pathogens.
The cytokines released by the activated T cells produce a systemic inflammatory response similar to that found in severe infection.
Th17 cells have cell function lead to auto immunity and have a major role in host defense, particularly anti-fungal infections.
TH 17 cells can be drivers of a cytokine storm that is independent of interferon gamma.
B cells are not often associated with cytokine storm, however the cell depletion is effective in treating some cytokines storm disorders, such as human herpesvirus8 associated multicentric Caastleman’s disease: suggesting these cells are capable of initiating or propagating cytokine storm particularly when virally infected.
Iatrogenic causes of cytokines storm involve excessive T cell activation such as CAR T cell and anti-CD28 antibody therapy which point to ability to activate T cells in to initiate cytokines storm.
May be life-threatening or fatal.
The systemic inflammatory response is characterized by hypotension, pyrexia and chills.
May be associated with headache, nausea, asthenia, hypotension, increased ALT, increased AST, increased bilirubin.
DIC, capillary leak syndrome, and hemagophagocytic lymphohistiocytosis/macrophage activation syndrome has been reported.
Can cause life-threatening pulmonary edema.
Manifestations can be reduced by slowing the infusion, intravenous administration of an anti-histamine and a corticosteroid, and acetaminophen 500 mg by mouth 1 hour before infusion to prevent fever.
Overhydration must be corrected before the administration of the first dose.
How to manage cytokine release syndrome.
Closely monitoring for cytokine release syndrome and starting anticytokine therapy early can prevent life-threatening organ toxicities in recipients of chimeric antigen receptor (CAR) T-cell therapy
No evidence that early anticytokine therapy impairs antitumor response.
Cytokine release syndrome affects multiple organs, explaining its diverse symptomatology.
Fever and flu-like illness mark its onset of CRS.Life-threatening findings include wide pulse pressures, hypotension, ventricular strain, and capillary leak leading to pulmonary edema and hypoxia, coagulopathy, azotemia, hyperbilirubinemia, transaminitis, flushing, and rash.
Using a consistent CRS severity grading system enables physicians to treat rationally across trials and CAR T-cell therapies.
CRS severity system defines grade 1 CRS as flu-like symptoms and fever up to 41.5 degrees Celsius.
Patients with grade 1 CRS should receive antipyretics and analgesia as needed and should be monitored closely for infections and fluid imbalances.
Hypotension signifies progression beyond grade 1 CRS, Andy should receive no more than two to three IV fluid boluses and then should receive vasopressors.
Early treatment seems to be better, although it is not yet known if prophylactic tocilizumab or corticosteroids can prevent CRS symptoms before they start.
Grade 2 CRS defined as hypotension responsive to one low-dose pressor or to fluid therapy and hypoxia responsive to less than 40% oxygen therapy.
Patients with grade 2 CRS who also have comorbidities should receive tocilizumab – with or without corticosteroids.
Severe CRS often results from supraphysiologic release of interleukin 6, which induces not only classic IL-6 signaling but also proinflammatory trans-signaling across many cell types.
Tocilizumab reverses this process by binding and blocking the IL-6 receptor
Tocilizumab is the mainstay of treatment for severe cytokine release syndrome.
Patients with grade 3 CRS have hypotension requiring multiple or high-dose pressors and hypoxia requiring oxygen therapy.
The ultimate goal is to avoid grade 4 CRS.
Grade 4 organ toxicity, requires mechanical ventilation, and yields a poor prognosis despite vigilant supportive care, tocilizumab, and corticosteroids.