Table 2 Cytokine-release syndrome grading and management

From: Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

Grade 1 CRS

Grade 2 CRS

Grade 3 CRS

Grade 4 CRS

Signs and symptoms

• Temperature ≥38 °C

• No hypotension

• No hypoxia

• Grade ≤1 organ toxicitya

Any temperature and any of the following:

• Hypotension that responds to i.v. fluids or low-dose vasopressor treatment

• SpO2 <90% on room air: FiO2 requirement <40% to keep SpO2 >88%

• Grade 2 organ toxicitya

Any temperature and any of the following:

• Hypotension (age 1–10 years: SBP <(70 + (2 × age in years)) mmHg; age >10 years: SBP <90 mmHg) requiring high-dose or multiple vasopressors

• FiO2 requirement ≥40% and/or requiring BiPAP to keep SpO2 >88%

• Grade 3 organ toxicitya

• Grade 4 transaminitis (>20× ULN)

Any temperature and any of the following:

• Persistent hypotension despite fluid resuscitation and treatment with multiple vasopressors

• Requirement for invasive mechanical ventilation

• Grade 4 organ toxicitya (except grade 4 transaminitis)

Paediatric considerations

• Asymptomatic sinus tachycardia is defined by heart rates above the age-specific normal range or baseline values)

• Hypotension is defined as follows: SBP <(70 + (2 × age in years)) mmHg in patients aged 1–10 years; SBP <90 mmHg in patients aged >10 years

• Oliguria is defined as a urine output of <0.5 ml/kg per hour for 8 hours

• Anuria is defined as a urine output of <0.3 ml/kg per hour for 24 hours or 0 ml/kg per hour for 12 hours

Management

• Acetaminophen, as needed, for fever

• Evaluate for infectious aetiologies (blood and urine cultures and chest radiography)

• Consider broad-spectrum antibiotics and filgrastim (if patient is neutropenic)

• Assess for adequate hydration

• Consider anti-IL-6 therapy for persistent or refractory feverb

• Symptomatic management of constitutional symptoms and organ toxicities

• Manage according to recommendations for grade 1 CRS (if applicable)

• Administer i.v. fluid bolus of 10–20 ml/kg normal saline; repeat as necessary to maintain SBP above baseline or age-specific normal range

• For hypotension refractory to fluid boluses or hypoxia, consider anti-IL-6 therapy with i.v. tocilizumab (12 mg/kg for patients weighing <30 kg or 8 mg/kg for those weighing ≥30 kg, to a maximum of 800 mg per dose); repeat dose every 8 hours for up to 3 doses within 24 hours (but titrate frequency according to response)

• If hypotension persists after two fluid boluses and anti-IL-6 therapy, start vasopressors, transfer patient to PICU, and obtain echocardiogram

• Use supplemental oxygen as needed

• If patient is at high risk of severe CRSc, hypotension persists after anti-IL-6 therapy, or there are signs of hypoperfusion or rapid deterioration, use stress-dose hydrocortisone (12.5–25 mg/m2 per day divided every 6 hours; i.v. dexamethasone 0.5 mg/kg (maximum 10 mg per dose) every 6 hours; or methylprednisolone 1–2 mg/kg per day divided every 6–12 hours)

• Manage according to recommendations for grades 1 and 2 CRS

• Transfer patient to PICU and obtain echocardiogram, if not performed already

• Administer i.v. dexamethasone 0.5 mg/kg (maximum 10 mg per dose) every 6 hours; can increase dose to maximum of 20 mg every 6 hours if patient is refractory to lower dose (alternatively, methylprednisolone 1–2 mg/kg per day divided every 6–12 hours can be used)d

• Use supplemental oxygen, including high-flow oxygen delivery and non-invasive positive pressure ventilation

• Administer i.v. fluids, anti-IL-6 therapy, corticosteroids, and vasopressors and perform haemodynamic monitoring as described for grades 1, 2, or 3 CRS

• If low doses of corticosteroids do not lead to clinical improvement, consider high-dose methylprednisolone (1 g daily for 3 days followed by rapid taper on the basis of clinical response)

  1. Early recognition of cytokine-release syndrome (CRS) and appropriate intervention are essential to avoid life-threatening complications of this toxicity. CRS should be suspected if any of the above listed signs and symptoms are present within the first 3 weeks after chimeric antigen receptor (CAR) T cell therapy. CRS grading should be performed at least twice a day and when a change in the patient's clinical status occurs. BiPAP, bi-level positive airway pressure; FiO2, fraction of inspired oxygen; i.v., intravenous; PICU, paediatric intensive-care unit; SBP, systolic blood pressure; SpO2, peripheral capillary oxygen saturation; ULN, upper limit of normal.
  2. aGraded according to the Common Terminology Criteria for Adverse Events version 5.0 guidelines99.
  3. bFor example, persistent fever lasting >3 days or fever with a temperature of ≥39 °C for >10 hours that is unresponsive to acetaminophen.
  4. cPatients with early onset of CRS signs and symptoms (within 3 days of cell infusion), bulky disease, and comorbidities are at high risk of developing severe CRS.
  5. dSimultaneous administration of corticosteroids and anti-IL-6 therapy or waiting to see if the patient responds to anti-IL-6 monotherapy before administering corticosteroids are both reasonable approaches (strategy used might vary depending on the CAR T cell products and/or risk factors).
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