Cytokine Release Syndrome: What to Know

Laura Dorwart
·7 min read

Medically reviewed by Jurairat J. Molina, MD

Cytokine release syndrome (CRS) is a condition caused by certain medications, treatments, and infections. It happens when a large volume of proteins known as cytokines are suddenly released into the body.

Formerly used interchangeably with the term “cytokine storm,” CRS is a systemic inflammatory response syndrome (SIRS), an inflammatory condition that impacts all of the body’s systems. Typical symptoms include fever, a racing heart, low blood pressure, shortness of breath, and skin rash. In some cases, cytokine release syndrome can be severe or even fatal.

This article covers everything you need to know about cytokine release syndrome, including symptoms, treatment options, and prevention.

<p>Boyloso / Getty Images</p>

Boyloso / Getty Images

What Is a Cytokine?

Cytokines are tiny proteins that play an important role in the body’s immune response. They “tell” the immune system how to fight off pathogens and illnesses, such as viruses and cancer.

Examples include interleukins, which behave as messengers between illness-fighting white blood cells, and interferons, which help to improve the body’s ability to combat cancer cells. Some laboratory-made cytokines are used to treat cancer and other serious conditions.

Are There Different Stages of Cytokine Release Syndrome?

Established in 2014, the Revised Cardiac Risk Index, or the Lee criteria, assesses cardiac risk and includes the following five grades of cytokine release syndrome:

  • Grade 1: Grade 1 symptoms include mild, non life-threatening, flu-like symptoms, such as fatigue and a low-grade fever.

  • Grade 2: Grade 2 symptoms include moderate symptoms and a fever of over 100.4 degrees F. At this time, you may need to take medications to raise your blood pressure or receive oxygen therapy.

  • Grade 3: Grade 3 symptoms include elevated liver enzymes or problems with organ toxicity alongside a high fever. You may need multiple blood pressure medications and/or more aggressive oxygen therapy.

  • Grade 4: Grade 4 symptoms include a high fever and could require more medical assistance to breathe, such as mechanical ventilation. Symptoms can be life-threatening, such as organ failure.

  • Grade 5: CRS becomes fatal.

Cytokine Release Syndrome Symptoms

Cytokine release syndrome can affect the entire body. The most common symptoms of cytokine release syndrome include:

  • Fever

  • Myalgia (muscle pain)

  • Fatigue

  • Arthralgia (joint pain and stiffness)

  • Headache

  • Skin rash

  • Nausea

  • Vomiting

  • Lack of appetite

  • Diarrhea

Heart and Blood Vessels

As it progresses, cytokine release syndrome may start to affect the cardiovascular and circulatory systems, meaning it impacts the heart and blood vessels. Symptoms may range from mild to serious or even life-threatening. They may include:

Brain and Nervous System

In particular, cancer-fighting chimeric antigen receptor (CAR) T-cell therapies, which work to prevent infection and fight existing conditions, often lead to cytokine release syndrome with neurotoxicity. These are problems within the nervous system. Some possible neurological symptoms are:

  • Confusion

  • Psychotic symptoms, such as hallucinations

  • Muscle weakness and lack of coordination

  • Memory loss

  • Seizures

  • Aphasia (inability to communicate verbally)

Lungs

Many people have respiratory symptoms as a result of cytokine release syndrome, such as:

What Causes Cytokine Release Syndrome?

Cytokine release syndrome was first discovered in the 1990s after the introduction of certain types of immunotherapy, which work to treat cancer and other conditions by boosting the body’s natural immune response.

Cytokine release syndrome occurs when many cytokines flood the body at once, often after an infusion or injection of antibodies. This sends the body’s immune system into overdrive, prompting an inflammatory response. Medications that treat cancer by affecting the body’s T-cells can also lead to cytokine release syndrome.

Common triggers for cytokine release syndrome are:

  • Monoclonal antibody treatments, such as Blincyto (blinatumomab) and Rituxan (rituximab)

  • Bispecific T-cell engager antibodies, such as Talvey (Talquetamab-tgvs)

  • Certain chemotherapy drugs, such as Eloxatin (oxaliplatin)

  • Medications used as part of CAR T-cell therapy, such as Kymriah (tisagenlecleucel)

  • Certain types of viral infections that cause cytokines to be naturally released, such as influenza and COVID-19

How Is Cytokine Release Syndrome Diagnosed?

In addition to elevated levels of certain cytokines in your blood, some of the biomarkers of cytokine release syndrome that your healthcare provider may test for include:

  • Increased levels of ferritin, a protein that stores iron

  • Elevated liver enzymes

  • Elevated levels of creatinine, to determine kidney function

  • High levels of C-reactive protein (CRP), which indicate inflammation

  • Problems with blood-clotting

  • Thrombocytopenia (low blood platelet count)

Cytokine release syndrome can be confused with several other conditions, such as:

  • Sepsis

  • Adrenal insufficiency

  • Allergic reactions

  • Immunodeficiency disorders

Part of the diagnostic process for cytokine release syndrome involves ensuring the above conditions are not causing symptoms.

Cytokine Release Syndrome Requires Prompt Treatment

Cytokine release syndrome is treatable, but it needs to be addressed right away to prevent serious complications. Mild to moderate CRS can be treated primarily with supportive care to manage symptoms, such as intravenous (IV) fluids, antihistamines, antipyretics to reduce fever, or vasopressors to regulate blood pressure.

Low-flow oxygen therapy may be helpful in relieving mild respiratory symptoms. People who have trouble breathing on their own may require more intensive interventions, such as mechanical ventilation or a continuous positive airway pressure (CPAP) machine.

Actemra (tocilizumab), which works to suppress the immune system and reduce inflammation, has been found to help treat severe cytokine release syndrome in children over 2 years old and adult patients. Other medications that work similarly include:

  • Corticosteroids

  • Sylvant (siltuximab)

  • Kineret (anakinra)

Cytokines and COVID-19

Pro-inflammatory cytokines have been found to play a major role in the severity and duration of COVID-19. People who get CRS after developing COVID-19 tend to have a harder time with recovery from the virus, as well as more complications along the way.

People with other inflammatory disorders, such as rheumatoid arthritis (RA), and people who are immunocompromised due to health conditions or treatments are significantly more likely to experience cytokine release syndrome alongside COVID-19.

How to Prevent Cytokine Release Syndrome

There are several risk factors that may increase your risk of developing cytokine release syndrome after receiving immunotherapy or getting an infection, such as:

  • Being immunocompromised

  • Having diabetes

  • Having a comorbid (co-occurring) inflammatory disorder

  • Being 65 years old or older

  • Having late-stage cancer, especially if it involves the bone marrow

  • Having high levels of ferritin before undergoing treatment

  • Undergoing lymphodepletion before CAR T-cell therapy

  • Taking higher doses of immunotherapy medication

You are also more likely to develop a severe case of CRS if your symptoms begin within 72 hours or less of receiving treatment.

Both JAK/STAT (Janus kinase/signal transducer and activator of transcription protein) inhibitors, such as Jakafi (ruxolitinib), and LENZ (lenzilumab), a monoclonal antibody, are effective in preventing CRS among people receiving CAR T-cell therapy.

Some research also suggests prophylactic (preventive) treatment with Blincyto or systemic corticosteroids as a means of prevention.

When to Contact a Healthcare Provider

Getting early treatment is especially important in order to prevent existing cases of CRS from getting worse and becoming life-threatening. If you are going to undergo immunotherapy, discuss your concerns about CRS. Let your healthcare provider know about any other medications you’re taking, as well as your medical history.

If you’ve recently developed an infection or undergone a treatment that could cause CRS and develop potential symptoms, such as fatigue, fever, or shortness of breath, tell your healthcare provider right away.

Summary

Cytokine release syndrome occurs when a flood of cytokines is set loose into the body all at once, leading to a systemic inflammatory reaction. This often happens as a result of immunotherapy, although it can also occur due to infection. Many people with CRS only have mild to moderate flu-like symptoms, but others develop life-threatening complications such as kidney or liver failure.

If you suspect that you may have a high risk of developing CRS, talk to your healthcare provider right away about the best course of action. Early diagnosis and management of symptoms is key in preventing serious complications and reducing the severity and duration of the illness.

Read the original article on Verywell Health.