Cytokine Release Syndrome (CRS)

What is cytokine release syndrome?

Cytokine release syndrome (CRS) is a possible side effect of certain types of therapies, especially CAR T-cell therapy. CRS happens when certain immune cells become very active and release large amounts of proteins called cytokines into the blood.  

High levels of cytokines can cause widespread inflammation throughout the body. CRS often begins with fever and flu-like symptoms but can worsen quickly. If not diagnosed and treated early, CRS can become a serious medical emergency.  

CRS usually develops in the first 2 weeks after CAR T-cell therapy and some other immunotherapies that activate the immune system. Treatment for CRS focuses on supportive care, managing symptoms, and reducing inflammation. Your child may need steroid medicines or other medicines that lower the immune response. Some patients may need more intensive care. Sometimes, the immunotherapy may need to be stopped or changed.  

Your care team will tell you what CRS symptoms to watch for. Most patients recover without long-term problems, especially if CRS is treated early. However, CRS can be life-threatening. Tell your care team right away if your child develops symptoms of CRS or if their symptoms worsen quickly.

Symptoms of cytokine release syndrome

CRS usually develops within 1-14 days after therapy, depending on the treatment. Inflammation caused by CRS can affect many organs and body systems, including the: 

• Lungs 
• Brain and nervous system 
• Liver and kidneys 
• Gastrointestinal (GI) system   
• Heart and blood vessels 

Signs and symptoms of CRS include: 

• Fever above 100.4˚F (38˚C) 
• Feeling tired or weak 
• Trouble breathing or low oxygen levels 
• Low blood pressure or feeling dizzy or faint 
• Fast heart rate 
• Chills or shaking 
• Headache 
• Body aches 
• Nausea or vomiting 
• Diarrhea 

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Some patients may develop a related condition called Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). ICANS is a type of inflammation that affects the brain and nervous system. Signs and symptoms of ICANS may include: 

• Confusion 
• Acting differently than usual 
• Trouble speaking 
• Seizures 

Causes of cytokine release syndrome

Certain immune cells make cytokines, proteins that act as messengers that help control the body’s immune response. Some cancer treatments can cause cells to quickly release cytokines into the bloodstream. This excessive immune response is sometimes called a “cytokine storm” and can lead to CRS.  

CRS can occur after treatment with CAR T-cell therapy and some other immunotherapies and targeted therapies. Examples of medicines with a risk of CRS include: 

• Blinatumomab (Blincyto®) 
• Tisagenlecleucel (Kymriah®)
• Anti-thymocyte globulin (ATG; Atgam®)
• Alemtuzumab (Campath®)

Your care team will tell you if the treatment your child receives has a risk of CRS. 

Children with a large amount of cancer in their body (called a high disease burden or bulky disease) may have a higher risk of developing CRS. Severe infections and some inflammatory conditions can also cause CRS or similar symptoms.  

Diagnosis of cytokine release syndrome

There is no single test that can diagnose CRS. Your care team will look at your child’s symptoms, when symptoms started, the treatment your child received, and the results of physical exams and laboratory tests. 

Because the CRS symptoms can be similar to an infection or other side effects of treatment, several tests may be needed to help find the cause of your child's symptoms. 

Tests and monitoring for CRS may include: 

• Regular checks of vital signs, including:  
  • Temperature 
  • Heart rate 
  • Breathing rate 
  • Blood pressure  
  • Oxygen levels  
• Blood tests to check:  
  • Blood cell counts  
  • Kidney and liver function  
  • Electrolytes  
  • Inflammation markers, such as C-reactive protein (CRP) and ferritin 
  • Blood clotting 
• Tests for infection, if needed
• Neurologic (brain and nervous system) exams to watch for ICANS 

If your child has CRS, your care team will make the best treatment plan based on your child’s condition and the severity of the CRS. 

Health care providers grade CRS on a scale of 1 to 4, with Grade 1 being mild and Grade 4 being the most severe and life-threatening.  

• CRS Grade 1-2 (mild to moderate): Children with mild to moderate CRS are closely monitored and receive supportive care, such as IV fluids, oxygen, and medicines to treat symptoms as needed. 
• CRS Grade 3-4 (severe): Children with severe CRS may receive medicines to treat inflammation and may need care in an intensive care unit (ICU). Some children need breathing support or other treatments to support the heart, lungs, or other organs while they recover.  

Treatment of cytokine release syndrome

Treatment for CRS depends on how severe your child's symptoms are. The goals of treatment are to control inflammation, treat symptoms, and protect the body's organs while the immune system recovers. 

Monitoring 

Patients at risk for CRS need close monitoring, especially during the first few weeks after therapy. Your care team will let you know how long extra monitoring is needed.  

• You may receive a patient information card on CRS symptoms. Keep this card with you at all times. 
• Contact your care team right away if your child shows any symptoms listed. 

Your child will have regular outpatient clinic visits and lab tests to monitor symptoms and progress. Your care team may check:   

• Temperature, heart rate, breathing rate, blood pressure, and oxygen levels 
• Heart function 
• Blood tests to monitor inflammation, kidney and liver function, electrolytes, and blood clotting   
• Brain and nervous system function (to watch for ICANS) 

Supportive care and symptom management 

Medical care for CRS centers on managing your child’s symptoms. Supportive care may include: 

• IV fluids 
• Oxygen support 
• Medicines for fever 
• Medicines to support blood pressure, heart function, or kidney function 
• Blood product transfusions 

Children with severe CRS may need care in an ICU. In rare cases, dialysis to support kidney function or temporary breathing support with a ventilator or heart-lung machine (ECMO) may be needed.  

Medicine to prevent seizures 

Some children with CRS may also get ICANS and be at risk for brain and nervous system effects. To help prevent seizures, some children may receive medicines such as levetiracetam (Keppra®). 

Medicine to decrease the immune response

Your child may get medicines to lower their immune response. These may include: 

• Tocilizumab (Actemra®) or siltuximab (Sylvant®): Blocks interleukin-6 (IL-6), a protein involved in inflammation
• Methylprednisolone or dexamethasone: Corticosteroids that reduce the immune response 
• Other medicines as needed, depending on the severity of CRS or if your child is in a clinical trial where additional medicines are used. 

Prognosis for cytokine release syndrome

Most patients recover from CRS without long-term problems, especially when it is recognized and treated early. Severe CRS can cause serious complications that affect breathing, blood pressure, or how organs work. Prompt treatment and close monitoring can help reduce these risks. 

Your care team can help you understand: 

• Your child’s risk for CRS 
• What signs and symptoms to watch for 
• What to do if symptoms develop 

When to call your care team

Tell your care team right away if your child develops symptoms of CRS, especially a fever, or if symptoms get worse quickly. 

 Call 911 or go to the nearest emergency room right away if your child: 

• Has trouble breathing  
• Has a seizure 
• Is confused or hard to wake up 
• Passes out (faints) 

Early diagnosis and treatment can help prevent serious complications. 

Always follow the instructions given by your care team. Talk to your doctor or pharmacist if you have questions or concerns about the medicine your child received and possible side effects. 

Questions to ask your care team

• Is my child at risk for cytokine release syndrome? 
• When is cytokine release syndrome most likely to happen? 
• What symptoms should I watch for? 
• How long will my child need monitoring for CRS after treatment? 
• When should I call the care team, and when should I seek emergency care? 
• What treatments might my child need if they develop CRS? 

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