Cytokine release syndrome (CRS)

What is cytokine release syndrome?

Cytokine release syndrome (CRS) is a side effect of some cancer treatments, particularly types of immunotherapy treatment. It is a reaction that causes inflammation of the whole body. Doctors also call this a cytokine storm.

CRS happens when the cancer treatment stimulates the immune system to release large amounts of cytokines into the bloodstream. This happens very fast and can overwhelm the body. Cytokines play an important role in our immune system. They help the body with its immune response.

The symptoms can be mild. Or they may be severe and life threatening.

It can be hard for doctors to tell the difference between CRS and other conditions, such as an infection. So it's important to always let them know about any side effects that you have.

CRS can also happen as the body’s response to a severe infection. The information on this page is about cancer treatment causing CRS.

You’re looked after by healthcare professionals with experience in CRS. They monitor you closely before and after treatment for any signs of CRS.

Symptoms of cytokine release syndrome

Cytokine release syndrome can cause a range of symptoms. Symptoms can be different in people having the same treatment.

Most people have a high temperature (fever). More general symptoms can include:

• tiredness and weakness (fatigue)

• generally feeling unwell

• feeling shivery or shaking (chills)

• flu-like symptoms, such as loss of appetite, headaches, feeling sick, aches and pains in your muscles and joints

Other possible symptoms depend on which part of the body is affected. You might have symptoms affecting the:

• skin, such as a rash or skin blistering and swelling

• cardiovascular system - this includes the heart and network of blood vessels that transports blood around the body. Symptoms include dizziness and feeling faint due to low blood pressure or a fast heartbeat

• lungs, such as low oxygen levels making it difficult to breathe, fast breathing or a cough

• digestive system, such as feeling or being sick, diarrhoea or loss of appetite

• brain - these are also known as neurological side effects

Neurological side effects can include:

• headaches

• confusion

• difficulty in communicating

• difficulty in concentrating

• seeing things that aren’t there (hallucinating)

• changes to how alert or awake you are

• seizures (fits)

What treatment causes cytokine release syndrome?

The types of immunotherapy treatment that can cause CRS include:

• adoptive cell transfer, such as CAR T-cell therapy or tumour infiltrating lymphocytes (TILs)

• monoclonal antibodies (mAbs), including bispecific T cell engagers (BiTEs)

• checkpoint inhibitors

• cytokine drugs such as interleukin

• anti thymocyte globulin (ATG)

There are some other treatments that can cause CRS, such as the cancer drugs oxaliplatin and lenalidomide. But it is less common.

Find out more about these treatment types

Who is at risk of developing cytokine release syndrome?

Not everyone having these treatments will have CRS. But there are people who are at higher risk. Even if you have risk factors it doesn’t mean that you will definitely develop CRS. You might be at higher risk if:

• you have a large number of cancer cells

• you have a certain cancer type. For example, CRS is more common in acute lymphoblastic leukaemia (ALL) than myeloma

• you are older. Older people may have more severe symptoms of CRS compared to younger people

• you have had high dose treatment to remove your lymphocytes before CAR T-cell treatment

The type of CAR T-cells that you have can also increase the risk of developing CRS.

Your doctor will let you know more about your individual risk.

Grading cytokine release syndrome

Grading is a measure of how mild or severe your CRS is.

The grading score ranges from grade 1 to grade 4. Your grade helps your team to decide what action they should take next.

Planning treatment and cytokine release syndrome

Before you have cancer treatment, your healthcare teams plans where you are best to have it and if there is anything you will need before it.

You might need to stay in hospital while having treatment. This is to closely monitor you and treat any symptoms of CRS. You might have other treatments as an outpatient. Your healthcare team will go through what to watch out for and when to call your hospital advice line.

You may have medicines before treatment. This is to help prevent or lessen the side effects of treatments that are likely to cause CRS. These medicines might include one or more of the following:

• an antihistamine

• paracetamol

• a steroid, such as dexamethasone

Managing and treating cytokine release syndrome

Your healthcare team builds up a picture of what is happening and looks at the best treatment options. They need to balance treating the CRS and your cancer.

Treatment depends on:

• what has caused the CRS

• your symptoms

• if you have any other medical conditions

Your doctor might have to rule out other possible causes of your symptoms. For example, a high temperature could be caused by an infection as well as CRS. You might have antibiotics if it’s not clear if you have an infection. Or if your team are waiting for results of infection tests.

Your nurse might pause or slow the infusion down if you’re having symptoms during treatment.

You might need other treatments to help with your symptoms. Once your symptoms have settled, your nurse can restart or increase the speed of the infusion.

Other possible treatments for CRS include:

• medicine to bring your temperature down (anti pyretics), such as paracetamol

• fluids through a drip into your bloodstream

• steroids

• oxygen through a tube into your nose or through a mask

• antihistamines

• medicines to help increase your blood pressure (vasopressors)

• a medicine called tocilizumab

Tocilizumab is a type of monoclonal antibody. It works by blocking a specific cytokine called interleukin-6 (IL-6) that causes inflammation. By blocking this cytokine, it reduces inflammation.

If CRS doesn’t get better with tocilizumab, you might have a different medicine called anakinra. Anakinra is a type of cytokine immunotherapy treatment. It lowers the body’s immune response. It does this by blocking the cytokine interleukin-1 (IL-1).

High dependency unit or intensive care unit

If you get seriously unwell with CRS, you may need to go to the high dependency unit (HDU) or intensive care unit (ICU). Here the nurses monitor you very closely.

You move back to the ward once your CRS is under control and you don’t need such close monitoring.

Do you get cytokine release syndrome every time you have treatment?

CRS can happen more than once. It can depend on the type of treatment you are having and how you reacted before. With some treatments, such as glofitamab, the risk of getting CRS with your first infusion is high. So you stay in hospital until 24 hours after the end of your infusion. You might have the next dose over a few more hours if you developed symptoms.

You might have to stop treatment if you have very severe CRS symptoms or you keep getting grade 3 or more CRS. Your team will talk to you about your treatment options if this is the case.