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Cytokine Release Syndrome (CRS) Grade (ASTCT criteria)

Please note:

  • Other causes of fever/ haemodynamic instability e.g. sepsis can mimic CRS and should also be considered and treated

  • There should be a temporal relationship between initiation of immune therapy and symptom onset

  • CRS is less common beyond 14 days after treatment administration
Fever Defined as temperature ≥38oC, not attributable to any other cause.

In patients who have received anti-pyretic therapy or anti-cytokine therapy (e.g. tocolizumab or steroids), fever is no longer required to grade CRS severity.
≥38oC
Hypotension Hypotension should be defined on a case by case basis taking into account the patient's age and normal baseline.

For practical purposes, a patient requiring IV fluid boluses or vasopressor to maintain blood pressure is considered to have hypotension.
Absent
Not requiring vasopressors
Requiring 1 vasopressor with or without vasopressin
Requiring multiple vasopressors (excluding vasopressin)
Hypoxia A patient requiring supplemental oxygen to correct an oxygenation deficit is considered to have hypoxia.

Supplemental oxygen given for comfort should not be considered as meeting the criteria for hypoxia.
Absent
Requiring low flow Defined as oxygen delivered at ≤6L/min. nasal canula or blow by
Requiring high flow Defined as oxygen delivered at ≥6L/min. nasal canula, facemask, non-rebreather mask or Venturi mask
Requiring positive pressure (CPAP, BiPAP), intubation or mechanical ventilation
CRS Grade: 1

ASTCT CRS (Cytokine Release Syndrome) Grade calculator

Cytokine release syndrome (CRS) is a potential serious toxicity of any immune therapy that engages endogenous or infused T-cells. It is especially associated with adoptive cellular therapies such as chimeric antigen receptor T-cell (CAR-T) therapy.

CRS is characterised by fever and constitutional symptoms (malaise, anorexia and rigors) which may progress to a systemic inflammatory response resulting in hypotension, hypoxia and organ dysfunction.

In 2019 the American Society for Transplantation and Cellular Therapy (ASTCT) published an updated grading system to harmonise existing schemes based on consensus of expert opinion(1).

Management algorithms based on CRS grading have been proposed, with earlier use of anti-IL6 therapy tocilizumab increasingly suggested. The table below summarises a proposed recommendation on management according to CRS grading (2,3).

Please note that management of CRS is an emerging field and grading and management guidelines are expected to change in the near future. Please ensure to check latest guidelines.

The other major toxicity with cellular immune therapies is a neurotoxicity syndrome called ICANS. See also our calculator for the ASTCT ICANS grading system.
CRS Grade Management
1
  • Supportive measures including anti-pyretics and analgesia
  • Assess for sepsis and cover with broad spectrum antibiotics
  • Consider tocilizumab if fever lasts >3 days
2
  • IV fluid boluses to support BP
  • Tocilizumab if BP refractory to fluid boluses.
  • If hypotension persists after 2 fluid boluses and tocilizumab transfer to ITU and commence a vassopressor
  • Supplemental oxygen to correct hypoxia
3
  • IV fluid as above
  • Tocilizumab as above
  • Manage in ITU setting
  • Dexamethasone 10mg IV QDS
  • 1 vasopressor +/- vasopressin to support BP
  • Supplemental oxygen including high flow oxygen and non-invasive ventilation if required
4
  • IV fluid as above
  • Tocilizumab as above
  • Manage in ITU setting as above
  • Methylprednisilone 1g/day IV
  • Multiple vasopressors as required to support BP
  • Mechanical ventilation if required

References:
  1. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol blood marrow Transplant J Am Soc Blood Marrow Transplant. 2019;25(4):625-638. doi:10.1016/j.bbmt.2018.12.758
  2. Neelapu SS. Managing the toxicities of CAR T-cell therapy. Hematol Oncol. 2019;37(S1):48-52. doi:https://doi.org/10.1002/hon.2595
  3. Morris EC, Neelapu SS, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol. 2022;22(2):85-96. doi:10.1038/s41577-021-00547-6