Introduction
The human body needs to protect itself and fight against various foreign invaders such as bacteria, viruses, fungi, and toxins. In order to fight against such foreign invaders, the body has developed a defense system called the immune system. The body’s immune system comprises white blood cells, the lymphatic system, antibodies, the complement system, bone marrow, the thymus, the spleen, etc. With the help of all these components, the immune system identifies and kills foreign invaders. But sometimes, the immune system gets hyperactivated, resulting in attacking its body cells. Cytokine release syndrome is an example of a hyperactive immune system or immune response.
What Are Cytokines?
Cytokines are low molecular weight proteins that help in mediating inflammatory and immune reactions. It is secreted by both immune cells and non-immune cells of the body in response to several stimuli. Cytokines play a major role in inducing inflammation, and cellular and humoral response, help in controlling cell multiplication and differentiation, cell death, regulate hematopoiesis (the process of blood cellular formation), control cell replication, and apoptosis (cell death). The different types of cytokines are chemokines, interferon, lymphokines, interleukins, tumor necrosis factor (TNF), and colony-stimulating factor.
Cytokines are released in response to anybody's infection by bacteria, viruses, and other microorganisms. These cytokines help in signaling the immune system cells to fight against infections. Concentrations of cytokines are elevated in response to an infection or any autoimmune disorder. Abnormally elevated levels of cytokines in the body lead to a syndrome called cytokine release syndrome (CRS).
What Is Cytokine Release Syndrome (CRS)?
Cytokine release syndrome occurs when our immune system responds to an infection in a highly aggressive manner. It is also referred to as cytokine storm or hypercytokinemia sometimes. CRS occurs in response to any infection, immunotherapy such as CAR T-cell therapy, autoimmune disorders, etc. Non-specific symptoms like fever and fatigue joint pain are commonly seen in CRS, whereas severe CRS causes multiorgan dysfunction or failure. It is potentially a life-threatening condition and requires proper medical treatment.
What Causes Cytokine Release Syndrome?
The main causes of cytokine release syndrome include:
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Infections that are caused by a virus, or bacteria.
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Due to some immunotherapies such as T-cell transfer therapy, monoclonal antibody therapy, etc.
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Autoimmune disorders, such as rheumatoid arthritis (a chronic inflammatory disorder affecting joints of feet and hands), and systemic lupus erythematosus (an inflammatory disease that occurs when the body tissues are attacked b their own immune system).
What Are the Symptoms of Cytokine Release Syndrome?
The symptoms of cytokine release syndrome can vary from non-specific symptoms such as fever, fatigue, and nausea to severe life-threatening symptoms like multiorgan dysfunction or failure. The following are the symptoms seen in CRS.
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Fever or moderate flu-like symptoms.
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Fatigue.
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Loss of appetite and weight loss.
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Headache and dizziness.
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Joint and muscle pain.
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Nausea and vomiting.
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Cough.
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Skin rashes.
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Difficulty in breathing.
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Low blood pressure.
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Delirium (confusion).
CRS can cause severe symptoms depending on which body part or organ it affects. Severe CRS can even cause multiorgan dysfunction or failure leading to death in some cases. This system requires proper medical treatment and care.
How Is Cytokine Release Syndrome Diagnosed?
In order to diagnose CRS primarily, its underlying reason has to be diagnosed. The healthcare provider might suggest various tests to delineate the underlying factor that causes CRS. Some of the tests that healthcare providers might suggest for diagnosing CRS include:
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General body monitoring like checking for blood pressure, heart rate, respiratory rate, pulse, etc.
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Flow cytometry for cytokine analysis. It is a technique used to measure and detect the characteristics of particles or cells, especially in cancer patients.
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Other important tests of cytokine analysis include immunoassay (tests that diagnose disease based on the antibody reaction to an antigen).
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Complete blood cell count.
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Imaging tests like CT (computed tomography), MRI (magnetic resonance imaging), and X-rays in cases where CRS affects organs like the heart, lungs, and brain.
What Are the Different Grades of Cytokine Release Syndrome?
The different grades of cytokine release syndrome are as follows:
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Grade 1: Only mild symptoms are observed. Monitoring of health status and symptomatic management (for example, medications for pain, antipyretics, and antiemetics) is only required.
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Grade 2 (Moderate Symptoms): Hypotension is seen and requires vasopressor for less than 24 hours or hypoxia (lack of enough oxygen) or dyspnea (shortness of breath) requiring supplemental oxygen (less than 40 percent up to six liters by nasal cannula).
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Grade 3 (Severe Symptoms): Hypotension requiring vasopressors for greater than or equal to 24 hours or hypoxia or dyspnoea requiring supplemental oxygen of more than 40 percent.
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Grade 4: Life-threatening symptoms are seen, like hypotension (low blood pressure) refractory to vasopressors or dyspnea, or hypoxia requiring mechanical ventilation.
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Grade 5: Leads to death.
How to Treat Cytokine Release Syndrome?
CRS should be treated timely and effectively as it can be life-threatening at times. A proper consultation with a healthcare provider is valuable in treating CRS better. The treatment options may vary depending on the severity of the condition. The healthcare provider diagnoses the symptoms and, based on that, suggests the best treatment option. The various treatment options include;
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Anti-inflammatory medications to reduce pain. Corticosteroids can also be given to reduce pain.
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Some drugs that target specific cytokines like Tocilizumab (Interleukin-6 receptor blocker), Siltuximab, and Anakinra.
Some of the treatment options that are given based on the severity include:
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IV (intravenous) fluids.
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Antipyretic drugs to reduce fever.
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Blood transfusions.
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Supplemental oxygen therapy.
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Mechanical ventilation.
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Dialysis in CRS affects the kidneys.
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Medications to treat cardiac-related symptoms caused by CRS.
What Is the Impact of Cytokine Release Syndrome in COVID-19 Patients?
COVID-19 (Coronavirus Disease 2019) has become one of the risk factors for developing a hyperactive immune response in COVID-affected patients. Due to this, too many cytokines are released into the body, causing a cytokine storm in the body. Detection of high levels of proinflammatory cytokine IL-6 in the blood of COVID-19 patients is seen. However, the exact cause of the release of high levels of cytokines is unknown. CRS induces ARDS (acute respiratory distress syndrome) and is one of the major causes of death in COVID-affected individuals. Two phases are exhibited in the COVID-19 patient as a result of the immune response to SARS-CoV-2. That includes:
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Phase 1: In this phase, the cytokine is released in response to eliminating the virus. During this phase, it is highly beneficial to use medicines that stimulate an immune response.
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Phase 2: These phases represent the severe symptomatic stage of COVID, where elevated levels of cytokines are released in the body. This leads to a cytokine storm in the body. Due to this, there is destruction and inflammation of lung tissues are seen and induce ARDS leading to death.
To detect cytokine levels in COVID patients, tests like serum tests, flow cytometry, and bronchoalveolar lavage fluid samples of patients are undertaken. Treating cytokine storms in COVID patients relies mainly on the cytokines involved and the mechanism causing cytokine storms. Targeted cytokine therapies like Tocilizumab (IL-6 inhibitor) are preferred mainly. Broad anti-inflammatory drugs are also given, but it leads to chances of secondary infection.
Conclusion:
Cytokine release syndrome is a systemic inflammatory syndrome that occurs as a result of the hyperactivated immune response. It is a life-threatening complication, and it ultimately leads to death in some cases. Requirement of proper medical treatment is necessary. The treatment options are only suggested by a healthcare provider based on the severity of the disease.
