Cytokine release syndrome
|Cytokine release syndrome (CRS)|
|Classification and external resources|
Cytokine release syndrome 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. CRS is sometimes referred to as an "infusion reaction".
- Grade 1: Mild reaction, infusion interruption not indicated; intervention not indicated
- Grade 2: Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated for <=24 hrs
- Grade 3: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates)
- Grade 4: Life-threatening consequences; pressor or ventilatory support indicated
- Grade 5: Death
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 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.
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). Cytokine storm may also be induced by certain medications, such as the CD20 antibody rituximab and the CD19 antibody tisagenlecleucel. The experimental drug TGN1412 caused extremely serious symptoms when given to six participants in a Phase I trial.
CRS needs to be distinguished from symptoms of the disease itself and in the case of drugs, from other adverse effects -- for example tumor lysis syndrome requires different interventions. As of 2015, differential diagnoses depended on the judgement of doctor as there were no objective tests.
Treatment for less severe CRS is supportive, addressing the symptoms like fever, muscle pain, or fatigue. Moderate CRS requires oxygen therapy and giving fluids and antihypotensive agents to raise blood pressure. For moderate to severe CRS, the use of immunosuppressive agents like corticosteroids may be necessary, but judgement must be used to avoid negating the effect of drugs intended to activate the immune system.
Although frequently used to treat severe CRS in people with ARDS, corticosteroids and NSAIDs have been evaluated in clinical trials and have shown no effect on lung mechanics, gas exchange, or beneficial outcome in early established ARDS.
In vitro assays have been developed to understand the risk that pre-clinical drug candidates might cause CRS and guide dosing for Phase I trials, and regulatory agencies expect to see results of such tests in investigational new drug applications.
Severe CRS is rare. Minor and moderate CRS are common side effects of immune-modulating antibody therapies and CAR-T therapies; 
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. 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.
It is believed that cytokine storms were responsible for the disproportionate number of healthy young adult deaths during the 1918 influenza pandemic, which killed 50 to 100 million people. In this case, a healthy immune system may have been a liability rather than an asset. Preliminary research results from Hong Kong also indicated this as the probable reason for many deaths during the SARS epidemic in 2003. Human deaths from the bird flu H5N1 usually involve cytokine storms as well. Cytokine storm has also been implicated in hantavirus pulmonary syndrome.
In 2006, a medical study at Northwick Park Hospital in England resulted in all 6 of the volunteers given the drug TGN1412 becoming critically ill, suffering from multiple organ failure, pyrexia, and a systemic inflammatory response. Parexel, a company conducting trials for pharmaceutical companies, in one of its own documents, wrote about the trial and said TGN1412 could cause a cytokine storm—the dangerous reaction the men experienced.
This article incorporates public domain material from the United States Department of Health and Human Services document "Common Terminology Criteria for Adverse Events (CTCAE) Version v4.03".
- Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL (July 2014). "Current concepts in the diagnosis and management of cytokine release syndrome". Blood. 124 (2): 188–95. doi:10.1182/blood-2014-05-552729. PMC . PMID 24876563.
- Kroschinsky F, Stölzel F, von Bonin S, Beutel G, Kochanek M, Kiehl M, Schellongowski P (April 2017). "New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management". Critical Care. 21 (1): 89. doi:10.1186/s13054-017-1678-1. PMC . PMID 28407743.
- Vidal JM, Kawabata TT, Thorpe R, Silva-Lima B, Cederbrant K, Poole S, Mueller-Berghaus J, Pallardy M, Van der Laan JW (August 2010). "In vitro cytokine release assays for predicting cytokine release syndrome: the current state-of-the-science. Report of a European Medicines Agency Workshop". Cytokine. 51 (2): 213–5. doi:10.1016/j.cyto.2010.04.008. PMID 20471854.
- Vogel WH (April 2010). "Infusion reactions: diagnosis, assessment, and management". Clinical Journal of Oncology Nursing. 14 (2): E10–21. doi:10.1188/10.CJON.E10-E21. PMID 20350882.
- "Common Terminology Criteria for Adverse Events (CTCAE) Version v4.03" (PDF). National Institutes of Health and National Cancer Institute. June 14, 2010. p. 66.
- Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ (2016). "Toxicity and management in CAR T-cell therapy". Molecular Therapy Oncolytics. 3: 16011. doi:10.1038/mto.2016.11. PMC . PMID 27626062.
- Murphy K, Travers P, Walport M (2007). "Signaling Through Immune System Receptors". Janeway's Immunobiology (7th ed.). London: Garland. ISBN 0-8153-4123-7.
- Drazen JM, Cecil RL, Goldman L, Bennett JC (2000). Cecil Textbook of Medicine (21st ed.). Philadelphia: W.B. Saunders. ISBN 0-7216-7996-X.
- "Guidance for Industry Immunogenicity Assessment for Therapeutic Protein Products" (PDF). FDA. August 2014.
- Clark IA (June 2007). "The advent of the cytokine storm". Immunology and Cell Biology. 85 (4): 271–3. doi:10.1038/sj.icb.7100062. PMID 17551531.
- Ferrara JL, Abhyankar S, Gilliland DG (February 1993). "Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1". Transplantation Proceedings. 25 (1 Pt 2): 1216–7. PMID 8442093.
- Osterholm MT (May 2005). "Preparing for the next pandemic". The New England Journal of Medicine. 352 (18): 1839–42. doi:10.1056/NEJMp058068. PMID 15872196.
- Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, Lei HY (February 2005). "An interferon-gamma-related cytokine storm in SARS patients". Journal of Medical Virology. 75 (2): 185–94. doi:10.1002/jmv.20255. PMID 15602737.
- Haque A, Hober D, Kasper LH (October 2007). "Confronting potential influenza A (H5N1) pandemic with better vaccines". Emerging Infectious Diseases. 13 (10): 1512–8. doi:10.3201/eid1310.061262. PMC . PMID 18258000.
- Mori M, Rothman AL, Kurane I, Montoya JM, Nolte KB, Norman JE, Waite DC, Koster FT, Ennis FA (February 1999). "High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome". The Journal of Infectious Diseases. 179 (2): 295–302. doi:10.1086/314597. PMID 9878011.
- "High stakes, high risks". The Lancet. Oncology. The Lancet. 8 (2): 85. February 2007. doi:10.1016/S1470-2045(07)70004-9. PMID 17267317.
- Coghlan A (2006-08-14). "Mystery over drug trial debacle deepens". Health. New Scientist. Retrieved 2009-04-29.