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    Patent Pending

    Cytokine Release Syndrome (CRS) Grading

    Assesses severity of CRS in patients on immunotherapy.
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    INSTRUCTIONS

    Use in patients receiving immunotherapy for cancer.

    When to Use
    Pearls/Pitfalls
    Why Use

    Patients receiving immunotherapy for cancer with signs of cytokine-mediated immunological reactions and multi-organ dysfunction.

    • Do not forget coagulopathy as organ dysfunction.

    • High-dose vasopressors need to be on board for ≥3 hours in order to be assigned grade 3.

    • Consider corticosteroids at 24 hours if no improvement.

    • Most patients receiving immunological therapies have complicated ongoing processes and require specialized care. Clinical expertise, vigilance, and frequent follow-up are key to recognizing CRS and not attributing signs and symptoms to an alternate cause (e.g. infection).

    Helps guide interventions for patients receiving immunological therapies for cancer.

    Symptoms not life-threatening; only symptomatic treatment required (fever, nausea, fatigue, headache, myalgias, malaise)
    Moderate intervention required for response: oxygen requirement <40%, hypotension responsive to fluids, low dose of one pressor, or grade 2 organ toxicity
    Aggressive intervention required for response: oxygen requirement ≥40%, hypotension requiring high dose/multiple pressors, grade 3 organ toxicity, or grade 4 transaminitis
    Life-threatening symptoms: ventilator required, or grade 4 organ toxicity (excluding transaminitis)
    Death

    Result:

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    Next Steps
    Evidence
    Creator Insights

    Advice

    Clinical judgment should be exercised at all times regarding the observed time course of symptoms and the patient's functional reserve. Tailoring interventions and moving to second-line agents, ruling out other causes, and follow-up are key.

    Management

    • Monitoring and aggressive supportive care should be considered in order to prevent irreversible end-organ damage.

    • Consider ICU setting (1:1 nursing care).

    • Consider involving expert consultative services.

    Critical Actions

    Always investigate for alternate causes such as infection, tumor lysis syndrome, or organ dysfunction. Always evaluate for end-organ damage.

    Formula

    Selection of the appropriate symptoms/signs:

    Toxicity

    Grade

    Symptoms not life-threatening; only symptomatic treatment required (fever, nausea, fatigue, headache, myalgias, malaise)

    1

    Moderate intervention required for response: oxygen requirement <40%, hypotension responsive to fluids, low dose of one pressor, or grade 2 organ toxicity

    2

    Aggressive intervention required for response: oxygen requirement ≥40%, hypotension requiring high dose/multiple pressors*, grade 3 organ toxicity, or grade 4 transaminitis

    3

    Life-threatening symptoms: ventilator required, or grade 4 organ toxicity (excluding transaminitis)

    4

    Death

    5

    Grade organ toxicity by Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

    *High dose pressors defined as any of the following for ≥3 hours:

    Pressor

    Dose**

    Monotherapy

    Norepinephrine

    ≥20 μg/kg/min

    Dopamine

    ≥10 μg/kg/min

    Phenylephrine

    ≥200 μg/kg/min

    Epinephrine

    ≥10 μg/kg/min

    If on vasopressin

    Vasopressin + norepinephrine equivalent of ≥10 μg/kg/min

    If on combination pressors (excluding vasopressin)

    Norepinephrine equivalent of ≥20 μg/kg/min

    **VASST Trial vasopressor equivalent equation: norepinephrine equivalent dose = [norepinephrine (μg/min)] + [dopamine (μg/kg/min) / 2] + [epinephrine (μg/min)] + [phenylephrine (μg/min) / 10].

     

    Facts & Figures

    Interpretation:

    CRS Grade

    Treatment

    Grade 1 CRS

    Vigilant supportive care, assess for infection (treat fever and neutropenia if present; monitor fluid balance; give antipyretics/analgesics as needed)

    Grade 2 CRS, no extensive comorbidities or older age

    Vigilant supportive care (monitor cardiac and other organ function closely)

    Grade 2 CRS with extensive comorbidities or older age

    Vigilant supportive care, tocilizumab ± corticosteroids

    Grade 3-4 CRS

    Grade 5

    Not applicable

    From Lee 2014.

    Evidence Appraisal

    The interventions listed are based on institutional practices where these therapies have been developed. They have been widely adopted and used in the clinical trials for these therapies. They are also included in the FDA labels of some of these medications.

    Dr. Daniel W. Lee

    About the Creator

    Daniel W. Lee, MD, is a pediatric oncologist and leading researcher at the University of Virginia’s Pediatric Stem Cell Transplant Program. He has also worked as a researcher at the National Cancer Institute’s Center for Cancer Research. Dr. Lee’s research focuses primarily on pediatric immunotherapy.

    To view Dr. Daniel W. Lee's publications, visit PubMed

    Content Contributors
    • Joseph Maakaron, MD
    About the Creator
    Dr. Daniel W. Lee
    Content Contributors
    • Joseph Maakaron, MD