Cytokine release syndrome (CRS) is a condition caused by certain drugs, treatments, and infections. This occurs when large amounts of proteins known as cytokines are suddenly released into the body.
Previously used interchangeably with the term “cytokine storm,” CRS is systemic inflammatory response syndrome (SIRS), an inflammatory disease that affects all systems in the body. Common symptoms include fever, racing heart, low blood pressure, shortness of breath, and skin rash. In some cases, cytokine release syndrome can be serious or even fatal.
This article covers everything you need to know about cytokine release syndrome, including symptoms, treatment options, and prevention.
What are Cytokines?
Cytokines are small proteins that play an important role in the body's immune response. They “tell” the immune system how to fight off pathogens and diseases such as viruses and cancer.
For example: interleukinActs as a messenger between disease-fighting white blood cells, interferon, which helps improve the body's ability to fight cancer cells. Some laboratory-made cytokines are used to treat cancer and other serious diseases.
A word from Berrywell
Symptoms can range from mild flu-like symptoms to severe, life-threatening symptoms. Cytokine release syndrome is treatable. If you have risk factors and develop symptoms suggestive of CRS after a COVID-19 infection or have received an infusion or injection of antibody immunotherapy, contact your healthcare provider immediately.
Are there different stages of cytokine release syndrome?
The Revision Cardiac Risk Index, or Lee criteria, established in 2014, assesses cardiac risk and includes five grades of cytokine release syndrome:
- 1 Grade: Grade 1 symptoms include mild, non-life-threatening flu-like symptoms such as fatigue and mild fever.
- 2nd grade: Second-degree symptoms include moderate symptoms and a fever of 100.4 degrees Fahrenheit or higher. At this time, you may need to take medication or receive oxygen therapy to raise your blood pressure.
- 3rd year: Grade 3 symptoms include organ toxicity issues along with elevated liver enzymes or high fever. Multiple blood pressure medications and/or more aggressive oxygen therapy may be needed.
- Grade 4: Grade 4 symptoms include high fever and may require more medical assistance, such as mechanical ventilation, to breathe. Symptoms can be life-threatening, including organ failure.
- 5th grade: 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
- Muscle pain (muscle pain)
- fatigue
- Joint pain (joint pain and stiffness)
- headache
- skin rash
- sickness
- throw up
- loss of appetite
- diarrhea
heart and blood vessels
As it progresses, cytokine release syndrome may begin to affect the cardiovascular and circulatory systems, meaning it affects the heart and blood vessels. Symptoms can range from mild to serious and even life-threatening. These may include:
brain and nervous system
In particular, cancer-fighting chimeric antigen receptor (CAR) T-cell therapy, which prevents infections and fights existing diseases, often causes cytokine release syndrome with neurotoxicity. This is a problem within the nervous system. Possible neurological symptoms include:
- delirium
- Psychotic symptoms such as hallucinations
- Muscle weakness and lack of coordination
- memory loss
- seizure
- Aphasia (inability to communicate verbally)
lung
Many people experience respiratory symptoms due to cytokine release syndrome, including:
What Causes Cytokine Release Syndrome?
Cytokine release syndrome was first discovered in the 1990s following the introduction of certain types of immunotherapy that treat cancer and other diseases by boosting the body's natural immune response.
Cytokine release syndrome occurs when many cytokines flood the body at once, often after an antibody infusion or injection. This sends the body's immune system into overdrive, causing an inflammatory response. Drugs that treat cancer by affecting the body's T cells can also cause cytokine release syndrome.
Common triggers for cytokine release syndrome include:
- 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)
- Drugs used as part of CAR T cell therapy, such as Kymriah (tisagenlecleucel)
- Certain types of viral infections that cause the natural release of cytokines, such as influenza and COVID-19
How is cytokine release syndrome diagnosed?
In addition to elevated levels of certain cytokines in the blood, some biomarkers of cytokine release syndrome that your healthcare provider may test for include:
- Increased levels of ferritin, a protein that stores iron
- increased liver enzymes
- Elevated creatinine levels to determine kidney function
- High levels of C-reactive protein (CRP), indicating inflammation
- blood clotting problems
- Thrombocytopenia (thrombocytopenia)
Cytokine release syndrome can be confused with several other disorders, including:
- Corruption
- adrenal insufficiency
- allergic reaction
- immunodeficiency disorder
Part of the process of diagnosing cytokine release syndrome includes determining whether any of the above conditions are causing the symptoms.
Cytokine release syndrome requires immediate treatment
Cytokine release syndrome is treatable but must be addressed promptly 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, or vasopressors to control blood pressure.
Low-flow oxygen therapy may help relieve mild respiratory symptoms. People who have trouble breathing on their own may need more intensive interventions, such as mechanical ventilation or continuous positive airway pressure (CPAP) machines.
Actemra (tocilizumab), which works by suppressing the immune system and reducing inflammation, has been shown to be helpful in treating severe cytokine release syndrome in children aged 2 years and older and in adult patients. Other drugs that act similarly include:
- corticosteroids
- Sylvant (siltuximab)
- Kineret (anakinra)
Cytokines and COVID-19
Pro-inflammatory cytokines have been shown to play an important role in the severity and duration of COVID-19. People who develop CRS after developing COVID-19 tend to have a harder time recovering from the virus and suffer more complications along the way.
People with other inflammatory diseases, such as rheumatoid arthritis (RA), and people who are immunocompromised due to a medical condition or treatment, are much more likely to experience cytokine release syndrome with COVID-19.
How to Prevent Cytokine Release Syndrome
Some risk factors that may increase your risk of developing cytokine release syndrome after receiving immunotherapy or developing an infection include:
- decreased immunity
- If you have diabetes
- If there is a concurrent (occurring at the same time) inflammatory disease
- 65 years or older
- If you have terminal cancer (especially if it involves the bone marrow)
- If your ferritin level was high before treatment
- If you are experiencing lymphocyte deficiency before CAR T cell therapy
- Taking high doses of immunotherapy drugs
You are also more likely to develop a severe case of CRS if your symptoms begin within 72 hours of receiving treatment.
JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription Proteins) inhibitors, such as Jakafi (ruxolitinib) and the monoclonal antibody LENZ (lenzilumab), are both effective in preventing CRS in people receiving CAR T cell therapy.
Some studies suggest prophylactic (prophylactic) treatment with Blincyto or systemic corticosteroids as a preventative measure.
When to contact your health care provider
Getting early treatment is especially important to prevent existing cases of CRS from worsening and becoming life-threatening. If you are planning to receive immunotherapy, discuss any concerns you have about CRS. Tell your health care provider about other medications you are taking and your medical history.
Tell your healthcare provider right away if you have recently had or been treated for an infection that may cause CRS and are experiencing potential symptoms, such as fatigue, fever, or difficulty breathing.
summary
Cytokine release syndrome occurs when a flood of cytokines rush into the body, causing a systemic inflammatory response. This commonly occurs as a result of immunotherapy, but can also occur due to infection. Many people with CRS have only mild to moderate flu-like symptoms, but others develop life-threatening complications, such as kidney or liver failure.
If you suspect you are at high risk for developing CRS, talk to your health care provider right away about the best course of action. Early diagnosis and management of symptoms are important to prevent serious complications and reduce the severity and duration of the disease.