From the Guidelines
Cytokine release syndrome (CRS) presents with a constellation of symptoms ranging from mild to life-threatening, including fever, fatigue, headache, rash, muscle and joint pain, nausea, vomiting, and diarrhea, as well as more severe manifestations such as hypotension, tachycardia, hypoxia, respiratory distress, and altered mental status, as reported in the most recent guidelines 1. The symptoms of CRS can be progressive and may include capillary leak syndrome, coagulopathy, multi-organ dysfunction, and cardiovascular collapse. According to the NCCN guidelines, version 1.2022, CRS grading is driven by hypotension or hypoxia, and fever is not required to grade subsequent CRS severity 1. Some key symptoms and their corresponding grades are:
- Grade 1: Fever (≥38°C)
- Grade 2: Hypotension requiring a vasopressor with or without vasopressin and/or hypoxia
- Grade 3: Fever with hypotension requiring a vasopressor with or without vasopressin and/or hypoxia
- Grade 4: Fever with hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure (eg, CPAP, BiPAP, intubation, mechanical ventilation) The underlying mechanism of CRS involves excessive immune activation with massive release of inflammatory cytokines (including IL-6, TNF-alpha, and interferon-gamma) that trigger widespread inflammation, as described in the ASCO guideline 1. Early recognition of CRS is crucial, and prompt intervention with supportive care and targeted therapies like tocilizumab (an IL-6 receptor antagonist) can prevent progression to life-threatening stages, as recommended by the EBMT and EHA 1. Healthcare providers should monitor vital signs, oxygen saturation, and organ function closely in patients at risk for developing CRS. The most effective approach to managing CRS is to provide prompt and urgent intervention to prevent progression, as outlined in the NCCN guidelines, version 1.2022 1.
From the FDA Drug Label
1.6 Cytokine Release Syndrome (CRS) ACTEMRA® (tocilizumab) is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older.
The symptoms of Cytokine Release Syndrome (CRS) are not directly stated in the provided drug labels. However, it can be inferred that CRS is a severe or life-threatening condition, but the specific symptoms are not mentioned. 2 2
From the Research
Symptoms of Cytokine Release Syndrome (CRS)
The symptoms of CRS can vary in severity and may include:
- Fever, which can be very high and is often the first symptom to appear 3, 4, 5, 6, 7
- Fatigue 3, 4
- Headache 3, 4
- Rash 3, 4
- Arthralgia (joint pain) 3
- Myalgia (muscle pain) 3
- Nausea 4
- Chills 4
- Hypotension (low blood pressure) 4
- Tachycardia (rapid heart rate) 4, 7
- Asthenia (weakness) 4
- Scratchy throat 4
- Dyspnea (shortness of breath) 4
- Cognitive decline 7
- Multifocal T2 hyperintensities on brain MRI 7
Severe Symptoms of CRS
In severe cases, CRS can lead to life-threatening complications, including:
- Vasoplegic shock associating capillary leakage and respiratory distress 3
- Severe organ dysfunction 5, 6
- Persistent high fever and hyperinflammation 5
- Secondary organ dysfunction 5
Onset and Duration of CRS
CRS usually appears between 1 and 14 days after the infusion of cells and can last from 1 to 10 days 3. In some cases, it can be fatal 3.