Signs and symptoms
CRS can present with a variety of symptoms ranging from mild, flu-like symptoms to severe life-threatening manifestations.r
Many features of CRS mimic infection and health practitioners must be cautious and exclude other causes of fever, hypotension, haemodynamic instability and/or respiratory distress. Bacteraemia and other infections have been reported as concurrent with or even mistaken for CRS. Thus, a reasonable temporal relationship to the cell therapy must be present, and infection
must be considered in all patients presenting with CRS symptoms.r
Note: in moderate to severe cases CRS can be accompanied by clinical signs and laboratory abnormalities that resemble haemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS).r For HLH/MAS during CRS, treat as per CRS with addition of steroids.r
Grading
The assessment and grading of CRS varies considerably across different institutions and clinical trials. This document is based on the grading scale from ASTCT.
Table 1 - ASTCT consensus grading for CRSr
CRS Parameter |
Grade 1 |
Grade 2 |
Grade 3 |
Grade 4 |
Fever* |
Temperature ≥ 38°C |
Temperature ≥ 38°C |
Temperature ≥ 38°C |
Temperature ≥ 38°C |
|
With |
Hypotension |
None |
Not requiring vasopressors |
Requiring a vasopressor with or without vasopressin |
Requiring multiple vasopressors (excluding vasopressin) |
|
And/or# |
Hypoxia |
None |
Requiring low-flow nasal cannula^ or blow-by |
Requiring high-flow nasal cannula^, facemask, non-rebreather mask, or venturi mask |
Requiring positive pressure (e.g. CPAP, BiPAP, intubation and mechanical ventilation) |
Footnotes:
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.
*Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
#CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring one vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS.
^Low-flow nasal cannula is defined as oxygen delivered at ≤6L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6L/minute.
Immune effector cell-associated neurotoxicity syndrome (ICANS)
As well as CRS, neurological toxicities are another common toxicity that have been reported after administration of T-cell therapies. Neurologic symptoms may occur during or more commonly after CRS symptoms (rarely before), vary among patients and are distinct from CRS.r
See ID 3834 Neurotoxicity associated with CAR T-cell therapy for more information.