Cytokine storm

Cytokine release syndrome, also known as an infusion reaction, is a form of systemic inflammatory response syndrome that arises as a complication of some diseases or infections, and is also an adverse effect of some monoclonal antibody drugs, as well as adoptive T-cell therapies. Severe cases have been called cytokine storms. Cytokine release syndrome, also known as an infusion reaction, is a form of systemic inflammatory response syndrome that arises as a complication of some diseases or infections, and is also an adverse effect of some monoclonal antibody drugs, as well as adoptive T-cell therapies. Severe cases have been called cytokine storms. The term cytokine storm appears to have been first used in 1993 in a discussion of graft vs. host disease; CRS as an adverse effect has been known since the approval of the first monoclonal antibody drug, muromonab-CD3, which causes CRS, but people working in the field of drug development at biotech and pharmaceutical companies, regulatory agencies, and academia began to more intensely discuss methods to classify it and how to mitigate its risk following the disastrous 2006 Phase I clinical trial of TGN 1412, in which the six subjects experienced severe CRS. Symptoms include fever, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rashes, fast breathing, rapid heartbeat, low blood pressure, seizures, headache, confusion, delirium, hallucinations, tremor, and loss of coordination. Lab tests and clinical monitoring show low blood oxygen, widened pulse pressure, increased cardiac output (early), potentially diminished cardiac output (late), high nitrogen levels in blood, elevated D-dimer, elevated transaminases, factor I deficiency and excessive bleeding, higher-than-normal level of bilirubin. CRS occurs when large numbers of white blood cells, including B cells, T cells, and natural killer cells, macrophages, dendritic cells, and monocytes are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. This can occur when the immune system is fighting pathogens, as cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines. 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, was intended to suppress the immune system to prevent rejection of organ transplants, alemtuzumab against CD52 and used to treat blood cancers as well as multiple sclerosis and in organ transplants, rituximab against CD20 also used to treat blood cancers and auto-immune disorders, all cause CRS. Adoptive T-cell therapies with T-cells modified with chimeric antigen receptors (CAR-T) also causes CRS. It appears that interleukin 6 is a key mediator of CRS. Severe CRS or cytokine storms can occur in a number of infectious and non-infectious diseases including graft-versus-host disease (GVHD), acute respiratory distress syndrome (ARDS), sepsis, Ebola, avian influenza, smallpox, and systemic inflammatory response syndrome (SIRS). 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. Cytokine storm may also be induced by certain medications, such as the CD20 antibody rituximab and the CD19 CAR T cell tisagenlecleucel. The experimental drug TGN1412 caused extremely serious symptoms when given to six participants in a Phase I trial.