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Cytokine Release Syndrome (CRS) After Immunotherapy

What Is Cytokine Release Syndrome?

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.

Cytokine Release Syndrome Symptoms

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

Causes of Cytokine Release Syndrome

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.

  • Blinatumomab (Blincyto®) is a bispecific T-cell engager (BITE) monoclonal antibody. This medicine works by causing T cells to target a protein called CD19 found on some types of leukemia cells.
  • Tisagenlecleucel (Kymriah®) is a CAR T-cell immunotherapy. It works by engineering T cells to have special receptors called chimeric antigen receptors (CARs). These receptors help T cells recognize and attack cancer cells.

Currently, CAR T-cell immunotherapy in pediatric cancer is most often used in children with relapsed or refractory acute lymphoblastic leukemia (ALL).

Chimeric antigen receptor, or CAR T-cell therapy, is one treatment associated with cytokine release syndrome or cytokine storm. CAR T-cell therapy doctors return modified T cells to patients to recognize and attack cancer cells.

Chimeric antigen receptor, or CAR T-cell therapy, is one treatment associated with cytokine release syndrome. CAR T-cell therapy doctors return modified T cells to patients to recognize and attack cancer cells.

Cytokine Release Syndrome Treatment

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.

Laboratory Tests and Symptom Monitoring

Patients at risk for CRS should be monitored closely, especially during the first weeks after immunotherapy. 

Monitoring for CRS includes:

  • Body temperature
  • Breathing rate
  • Blood pressure
  • Heart rate
  • Oxygen levels
  • Neurological exam to watch for changes in brain and nervous system function
  • Laboratory tests such as blood counts, electrolytes, indicators of kidney and liver function, cytokines and other markers of immune function, and work-up for infection

Supportive Care and Symptom Management

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:

  • IV fluids
  • Oxygen or ventilator support
  • Medicines to regulate blood pressure
  • Medicines to support heart function
  • Blood product transfusions
  • Medicines or dialysis to support kidney function

Prevention of Seizures

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.

Medicines to Decrease the Immune Response

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.

A common cytokine target is interleukin-6 (IL-6). The drugs most often used to interfere with IL-6 are tocilizumab and siltuximab.

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.


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Reviewed: March 2019