Table 1. Previously Used Grading Systems for Cytokine Release Syndrome.
| CTCAE v4.03 | CTCAE v5.0 | Lee Criteria | Penn Criteria | MSKCC Criteria | CARTOX Criteria | |
|---|---|---|---|---|---|---|
| Grade 1 | Mild reaction; infusion interruption not indicated; intervention not indicated | Fever, with or without constitutional symptoms | Symptoms are not life-threatening and require symptomatic treatment only (fever, nausea, fatigue, headache, myalgias, malaise) | Mild reaction: Treated with supportive care, such as antipyretics, antiemetics | Mild symptoms requiring observation or supportive care only (e.g., anti-pyretics, antiemetics, pain medication) | Temperature ≥ 38°C Grade 1 organ toxicityb |
| Grade 2 | Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated for ≤ 24 h | Hypotension responding to fluids. Hypoxia responding to < 40% FiO2 | Symptoms require and respond to moderate intervention: | Moderate reaction: Some signs of organ dysfunction (grade 2 creatinine or grade 3 LFTs) related to CRS and not attributable to any other condition | Hypotension requiring any vasopressors < 24 h | Hypotension responds to IV fluids or low-dose vasopressor |
| • Oxygen requirement <40% FiO2 OR | Hospitalization for management of CRS-related symptoms, including neutropenic fever and need for IV therapies (not including fluid resuscitation for hypotension) | Hypoxia or dyspnea requiring supplemental oxygen < 40% | Hypoxia requiring FiO2 < 40% | |||
| • Hypotension responsive to IV fluids or low dose of one vasopressor OR | Grade 2 organ toxicity | |||||
| • Grade 2 organ toxicitya | ||||||
| Grade 3 | Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrate) | Hypotension managed with one pressor. Hypoxia requiring ≥ 40% FiO2 | Symptoms require and respond to aggressive intervention: | More severe reaction: Hospitalization required for management of symptoms related to organ dysfunction, including grade 4 LFTs or grade 3 creatinine, related to CRS and not attributable to any other condition | Hypotension requiring any vasopressors ≥ 24 h | Hypotension needing high-dose or multiple vasopressors |
| • Oxygen requirement ≥ 40% FiO2 OR | Hypotension treated with multiple fluid boluses or low-dose vasopressors | Hypoxia requiring FiO2 ≥ 40% | ||||
| • Hypotension requiring high-dose or multiple vasopressors OR | Coagulopathy requiring fresh frozen plasma, cryoprecipitate, or fibrinogen concentrate | Hypoxia or dyspnea requiring supplemental oxygen ≥ 40% | Grade 3 organ toxicityb or grade 4 transaminitis | |||
| • Grade 3 organ toxicitya or grade 4 transaminitis | Hypoxia requiring supplemental oxygen (nasal cannula oxygen, high-flow oxygen, CPAP, or BiPAP) | |||||
| Grade 4 | Life-threatening consequences; pressor or ventilatory support indicated | Life-threatening consequences; urgent intervention needed | Life-threatening symptoms: | Life-threatening complications such as hypotension requiring high-dose vasopressors | Life-threatening symptoms | Life-threatening hypotension |
| • Requirement for ventilator support OR | Hypoxia requiring mechanical ventilation | Hypotension refractory to high dose vasopressors | Needing ventilator support | |||
| • Grade 4 organ toxicitya (excluding transaminitis) | Hypoxia or dyspnea requiring mechanical ventilation | Grade 4 organ toxicityb except grade 4 transaminitis |
Note. NSAIDs = nonsteroidal anti-inflammatory drugs; LFTs = liver function tests; CPAP = continuous positive airway pressure; BiPAP = bilevel positive airway pressure. Adapted from Lee et al. (2019).
aAs per CTCAE version 4.03.
bCardiac (tachycardia, arrhythmias, heart block, low ejection fraction), respiratory (tachypnea, pleural effusion, pulmonary edema), gastrointestinal (nausea, vomiting, diarrhea), hepatic (increased serum alanine aminotransferase, aspartate aminotransferase, bilirubin level), renal (acute kidney injury, increased serum creatinine, decreased urine output), dermatologic (rash), or coagulopathy (disseminated intravascular coagulation; Lee et al., 2019).