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Cytokine release syndrome (CRS) is a collection of symptoms that can develop as a side effect of certain types of immunotherapy, especially those which involve T-cells. The syndrome occurs when immune cells are activated and release large amounts of cytokines into the body. Cytokines are small proteins that act as cell messengers to help direct the body’s immune response. However, high levels of cytokines may cause increased inflammation throughout the body. This can be harmful and interfere with a number of body functions. In severe cases, CRS can cause organ failure and even death.
CRS usually develops within 3-14 days after T cell based immunotherapy. It often begins with fever and flu-like symptoms but can worsen quickly and cause serious illness.
Management of CRS includes monitoring and supportive care to control symptoms. Some patients may need intensive care and medicines to lower the immune response (immunosuppressive drugs).
At-risk patients will be monitored for about a month after an immunotherapy infusion. Patients who develop symptoms usually improve within 1-2 weeks. Most patients do not have long-term problems from cytokine release syndrome.
Symptoms of CRS are caused by a widespread immune response in the body. Different organ systems can be affected with a range of symptoms. In some cases, CRS can cause life-threatening changes in heart, lung, kidney, liver, and brain function.
Many CRS symptoms can have other causes. Neurotoxicity and other side effects of immune therapies can happen with or without CRS symptoms. The care team will perform tests and monitor symptoms to plan the best course of treatment.
|Body System Affected||Possible Symptoms|
|General||Fever, chills, fatigue, weakness, loss of appetite, nausea, vomiting, diarrhea, headache, joint or muscle aches, skin rash|
|Heart and blood vessels||Low blood pressure, increased heart rate, irregular heartbeat, decreased heart function, swelling and buildup of fluids (edema)|
|Brain and nervous system||Headache, confusion, dizziness, seizures, hallucinations, decreased coordination, problems talking or swallowing, shaking, problems controlling movements|
|Lungs||Cough, shortness of breath, decreased lung function, reduced oxygen levels|
|Other changes and laboratory markers||Decreased kidney or liver function, increased cytokine levels in the blood, change in electrolytes, change in blood clotting|
Cytokine release syndrome occurs after treatment with immunotherapy that activates T cells to fight cancer. These therapies trigger a widespread immune inflammatory response due to the release of cytokines.
In childhood cancer, immunotherapies most often associated with CRS include blinatumomab and tisagnlecleucel.
Currently, CAR T-cell immunotherapy in pediatric cancer is most often used in children with relapsed or refractory acute lymphoblastic leukemia (ALL).
Management of CRS includes monitoring and laboratory tests, treating specific symptoms, and medicines to lower the immune response. The care team will watch for worsening of symptoms and signs of organ failure. Treatments are based on the severity or grade of cytokine release syndrome. Children with more extensive disease related to their cancer are at higher risk for more severe CRS.
Patients at risk for CRS should be monitored closely, especially during the first weeks after immunotherapy.
Monitoring for CRS includes:
Medical care for CRS centers on managing the patient’s specific symptoms. Some patients may need care in an ICU setting.
Supportive care may include:
Patients at risk for brain and nervous system effects may be given a medication such as levetiracetam (Keppra®) to help prevent seizures that can occur with immunotherapy.
Patients with severe CRS are treated with drugs that counteract the immune response. These medicines include targeted therapies to block specific cytokines, as well as more general immunosuppressive drugs.
Corticosteroids such as methylprednisolone or dexamethasone may also be used to help reduce inflammatory and immune responses; they do not target specific cytokines but rather provide broader immunosuppression.
Because immunosuppressive drugs have the potential to interfere with the anti-cancer effect of immunotherapy and also have other side effects, these medicines are not used in all cases.
The care team will weigh potential benefits and risks in deciding the best plan of treatment.
Cytokine release syndrome is a serious complication that can occur with immunotherapy. At-risk patients are monitored closely. Treatments focus on managing symptoms and supporting organ function.
Your doctor can help you understand cytokine release syndrome and know whether your child is at risk. Always talk to your care team about any health concerns, and report changes in symptoms that occur during or after treatment.
Together does not endorse any branded product mentioned in this article.
Reviewed: March 2019