Cytokine Release Syndrome
Excessive immune system activation following CAR T-cell therapy that occurs due to activation and proliferation of CAR T-cells:
- Occurs in 40-90% of cases
- Onset hours-days after administration
- Characterised by a raft of non-specific inflammatory symptoms:
- Fever
- Malaise
- Myalgia
- Tachycardia
- Rash
- Capillary leak syndrome
- Pulmonary oedema
- Multiorgan dysfunction
Epidemiology and Risk Factors
Pathophysiology
Aetiology
Assessment
Features of CRS relate to a global inflammatory state, and include:
- C
- ↑ HR
- CCF
- Arrhythmias
- Oedema secondary to capillary leak
- D
- Rash
- F
- AKI
- G
- Hepatic dysfunction
Deranged LFTs. - Nausea, vomiting
- Hepatic dysfunction
- H
- Cytopaenias
- DIC
- Macrophage activation HLH/
- ↑ Ferritin
- Coagulopathy
- Hepatic dysfunction
- Cytopenias
History
Examination
Investigations
Bedside:
Laboratory:
Imaging:
Other:
Diagnostic Approach and DDx
Cytokine release syndrome requires both:
- Fever (≥38.0°C) Cardinal sign common to all grades of CRS.
- Hypotension or hypoxaemia
Grade of CRS is determined by the degree of physiological support required.
- :::
- CRS Grading
| Grade | Hypotension (SBP <90mmHg) | Hypoxia |
| 1 | None | None |
| 2 | Not requiring vasopressors | Low-flow nasal oxygen (<6L/min) |
| 3 | Requiring 1 vasopressor (+/- vasopressin) | High-flow nasal oxygen Non-rebreather >6L/min Venturi >6L/min Face mask >6L/min |
| 4 | Requiring >1 vasopressor (excluding vasopressin) | Positive pressure ventilation |
:::
Management
- Rule out infective causes
- Give antipyretics
- Fluid resuscitation and vasopressors
- Immunomodulators
Dose and choice of agent depends on grade.
Note that the presence of ICANS supersedes the presence of CRS - immunomodulation therapy should be as per ICANS grading if both are present.
Resuscitation:
- C
- Fluid resuscitation
- Low threshold for vasopressors
CRS is associated with significant capillary leak - avoid >2L IVT/day.
Specific therapy:
Historical concern existed about the use of corticosteroids with CAR T-cell therapy, due to the risk of inducing T-cell apoptosis and subsequently ending the therapy by removing all the cells.
More recent data supports judicious use, however steroid dosing should be guided by the haematologist.
- Pharmacological
- Immunomodulators
- Grade 1:
- Tocilizumab 8mg/kg Q8H up to 3 doses
Human monoclonal IL-6 antibody.- Indicated for any patient requiring ICU admission
- Repeat once (i.e. 2 doses) if 1st dose ineffective
- Dexamethasone 4-10mg IV QID
- Tocilizumab 8mg/kg Q8H up to 3 doses
- Grade 2:
- Tocilizumab as per grade 1 (if not already given)
- Dexamethasone 10mg IV QID
- Consider anakinra 100-200mg IV BD-QID
- Grade 3-4:
- Tocilizumab as per grade 1 (if not already given)
- Dexamethasone as per grade 2, or consider high-dose methylprednisolone (1g daily, or 2mg/kg/day)
- Grade 1:
- Immunomodulators
- Procedural
- Physical
Supportive care:
Disposition:
- Disposition also depends on grade
- Grade 1: Appropriate for ward based care
- Grade 2: Consideration of HDU/higher-level care
- Grade 3-4: ICU admission
Preventative:
Marginal and Ineffective Therapies
Anaesthetic Considerations
Complications
Prognosis
Key Studies
References
- Messmer AS, Que YA, Schankin C, Banz Y, Bacher U, Novak U, et al. CAR T-cell therapy and critical care. Wien Klin Wochenschr. 2021 Dec 1;133(23):1318–25.