Cytokine release syndrome
Cytokine release syndrome | |
---|---|
Other names | Infusion-related reaction (IRR), infusion reaction,[1] cytokine storm[2] |
Specialty | Immunology |
In immunology, cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs.[3] It refers to cytokine storm syndromes (CSS)[4] and occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody medications, as well as adoptive T-cell therapies.[5][6] When occurring as a result of a medication, it is also known as an infusion reaction.[1]
The term cytokine storm is often used interchangeably with CRS but, despite the fact that they have similar
Signs and symptoms
Symptoms include fever that tends to fluctuate, 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.[5]
Lab tests and clinical monitoring show low blood oxygen, widened pulse pressure, increased cardiac output (early), potentially diminished cardiac output (late), high levels of nitrogen compounds in the blood, elevated D-dimer, elevated transaminases, factor I deficiency and excessive bleeding, higher-than-normal level of bilirubin.[5][8]
Cause
CRS occurs when large numbers of
This can occur when the
In addition to adoptive T-cell therapies, severe CRS or cytokine reactions can occur in a number of infectious and non-infectious diseases including
Although
Medications
Cytokine reaction syndrome may also be induced by certain medications, such as the
Diagnosis
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.[5]
Classification
CRS is a form of systemic inflammatory response syndrome and is an adverse effect of some drugs.[5]
The Common Terminology Criteria for Adverse Events classifications for CRS as of version 4.03 issued in 2010 were:[5][20]
Grades | Toxicity |
---|---|
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 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 |
Prevention
Severe CRS caused by some drugs can be prevented by using lower doses, infusing slowly, and administering
A modified Chandler loop model can be used as a preclinical tool to assess infusion reactions.[22]
Management
Treatment for less severe CRS is
Lenzilumab, an anti-GM-CSF monoclonal antibody, is also clinically proven to be effective at managing cytokine release by reducing activation of myeloid cells and decreasing the production of IL-1, IL-6, MCP-1, MIP-1, and IP-10. [23][24] Additionally, as a soluble cytokine blockade, it will not increase serum levels of GM-CSF (a phenomenon seen with tocilizumab and IL-6).[25]
Although frequently used to treat severe CRS in people with
Epidemiology
Severe CRS is rare. Minor and moderate CRS are common side effects of
Research
Key therapeutic targets to abrogate hyper-inflammation in CRS are IL-1, IL-6, and GM-CSF. An
See also
References
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- ^ "Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein Products" (PDF). FDA. August 2014.
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This article incorporates public domain material from Common Terminology Criteria for Adverse Events (CTCAE) Version v4.03 (PDF). United States Department of Health and Human Services.