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Cytokine Release Syndrome (CRS)

CRS is a potential serious adverse event of immunotherapies, particularly some T cell–engaging immunotherapies; risk mitigation and early recognition can reduce CRS severity and guide its management.

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Pathophysiology
Clinical Manifestations
Diagnosis
Grading
Management
Abbreviations

Pathophysiology

CRS Results From Hypersecretion of Cytokines That Mediate the Immune System​

Cytokines are a diverse group of polypeptide chemical messengers that are secreted by most cells in the body.1​ Cytokines include interleukin, interferon, tumor necrosis factor, lymphokines, monokines, and chemokines.

Cytokines play an integral role in:

Activated T cell with up and down arrows icon

Promoting or inhibiting ​cell growth

Activated T cell with outward arrows icon

Mediating​ the inflammatory response

Activated T cell with inward arrows icon

Activating​ immune effector cells

CRS is a supraphysiologic response resulting from the over-activation of endogenous or infused T cells and/or other immune effector cells, which in turn leads to hypersecretion of cytokines.1-3​ Symptoms depend on the extent and nature of the cytokine elevation2

CRS Comprises an Immune Chain Reaction, Leading to Increased Inflammation and Damage2,4

1 These cytokines trigger a chain reaction that involves the activation of innate immune cells, such as macrophages and endothelial cells, which results in the release of additional cytokines2

2 Activated endothelial cells release stored Ang2 and VWF, while macrophages trigger the production of NO, which promotes vasodilation and hypotension4

3 IL-6 is considered to be a central mediator of CRS and is thought to contribute to many of the key symptoms2

4 Additional and uncontrolled immune cell recruitment and activation then occur, resulting in the release of further cytokines4

References

  1. Breslin S. Clin J Oncol Nurs. 2007;11(1 Suppl):37-42.
  2. Shimabukuro-Vornhagen A, et al. J Immunother Cancer. 2018;6(1):56.
  3. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25(4):625-638.
  4. Cobb DA, Lee DW. Cancer J. 2021;27(2):119-125.

Clinical Manifestations

CRS Has a Diverse Presentation, With Symptom Severity Ranging From Mild to Severe ​and Potentially Life-Threatening1,2​

Considerations when evaluating patients for potential CRS

Mild Symptoms
  • Fever (≥38°C)
  • Cough
  • Tachycardia
  • Chills
  • Fatigue
  • Headache
  • Rash
  • Arthralgia
  • Myalgia
Severe Symptoms
  • Atrial fibrillation
  • Ventricular tachycardia
  • Cardiac arrest
  • Cardiac failure
  • Renal insufficiency
  • Capillary leak syndrome
  • Hypotension
  • Hypoxia
  • MAS/HLH

CRS Can Impact Multiple Organ Systems1​

Non-specific symptoms​

  • Fever (at onset)a​
  • Fatigue​
  • Anorexia

1 Brain: Headaches, confusion, hallucinations, delirium, aphasia, paresis, and seizures

2 Blood and vasculature: Cytopenias, coagulopathy (↑PTT ↓INR), febrile neutropenia, DIC, and capillary leak

3 Heart: Tachycardia, hypotension,a troponin elevation, arrhythmia, QT prolongation, stress cardiomyopathy, and acute heart failure

4 Liver: Hepatomegaly, elevated liver enzymes, hypofigrinogenemia, and liver failure

5 Colon: Diarrhea

6 Lungs: Tachypnea, hypoxia,a pulmonary edema, and respiratory failure

7 Spleen: Splenomegaly

8 Stomach: Nausea and vomiting

9 Kidneys: Acute kidney injury and renal failure

10 Joints, muscles, and skin: Myalgia, arthralgia, rigor, rash, and edema

Certain Treatment and Patient Factors May Influence the Clinical Presentation of CRS

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Immunotherapies
CRS is a potential adverse event with T-cell–engaging immunotherapies1

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Underlying disease
Disease burden can be a predictor of severe CRS3,4

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Patient characteristics (basal inflammatory state) and comorbidities
High baseline serum ferritin, CRP, or cytokine levels can be associated with increased CRS5,6

T cell and blood cell icon

Degree of T-cell activation and expansion
Onset of clinical symptoms of CRS may correlate with T-cell activation7,b

Footnotes

  1. Most common symptoms.
  2. There does not appear to be a direct association between the incidence and severity of CRS and response to immunotherapy.

References

  1. Shimabukuro-Vornhagen A, et al. J Immunother Cancer. 2018;6(1):56.
  2. Adkins S. J Adv Pract Oncol. 2019;10(suppl 3):21-28.
  3. Maude SL, et al. N Engl J Med. 2014;371(16):1507-1517.
  4. Park JH, et al. N Engl J Med. 2018;378(5):449-459.
  5. Teachey DT, et al. Cancer Discov. 2016;6(6):664-679.
  6. Davila ML, et al. Sci Transl Med. 2014;6(224):224ra25.
  7. Frey N, Porter D. Biol Blood Marrow Transpl. 2019;25(4):e123-e127.

Diagnosis

CRS May Be Diagnosed by Process of Exclusion​1

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Consider exclusion of anaphylactic reaction

  • Prior exposure ​
  • Response to antihistamines
Petri dish with bacteria icon

Consider exclusion of systemic infection​

  • Positive blood culture, ​X-ray, etc.​
  • Response to anti-infective treatment​
Cell with DNA and nucleus icon

Consider exclusion of tumor lysis syndrome

  • Hyperuricemia, hyperkalemia​
  • Hyperphosphatemia, hypocalcemia​
DNA helix icon

Consider exclusion of MAS/HLH

  • Family history of MAS/HLH​
  • Associated genetic aberrations with MAS/HLH
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Progression of the underlying malignancy should be considered if symptoms are mild​

ASTCT Consensus Definition of CRS2

CRS: A supraphysiologic response following the activation or engagement of T cells and other immune effector cells for therapeutic intent​

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MUST

include fever at onset and symptoms occurring within a reasonable time frame to therapy

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MAY

include hypotension, hypoxia, and end organ dysfunction

Yellow X icon

NOT

limited to only CAR T-cell therapies or defined by cytokine levels or lab tests

Differential Diagnosis of CRS Can Be Challenging​

As patients with CRS present with a wide range of signs and symptoms, accurate diagnosis can be challenging.3​

Differential diagnosis of CRS3-6

  • Allergic drug reaction
  • Tumor lysis syndrome
  • Heart failure
  • Infections
  • MAS/HLHa
  • Infusion-related reactions
  • Tumor progression
  • Thromboembolism

Neurologic AEs, such as headaches, confusion, dysphasia and ataxia, can occur alongside CRS in the context of ​T-cell–targeted immunotherapy.4,5

Recognizing whether symptoms are related to CRS or another condition is key to optimal management​

Infusion-Related Reactions May Be Clinically Indistinguishable From CRS6-9

Overlapping symptoms:

  • Chills​
  • Pyrexia​
  • Hypotension​
  • Tachycardia​
  • Nausea​
  • Vomiting​
  • Diarrhea​
  • Hypertension​
  • Hypoxia​
  • Tachypnea​
  • Headache
CRS7,8

CRS is a syndrome associated with therapies where there is a T-cell–mediated mechanism of action​
IRR6,9

IRR is a disorder characterized by adverse reaction to the infusion of pharmacological or biological substances and can also involve the release of cytokines​
  • Like CRS, IRRs may involve the release of cytokines and other factors6,7​
  • In some clinical studies, CRS events that arise during or shortly after infusion may fulfil the protocol-mandated definition of IRR, and be reported as such9

CRS May Also Present With Neurological Symptoms and Should Be Differentiated From ICANS2,4,10​

Overlapping symptoms:

  • Headache​
  • Confusion​
  • Dysphasia​
  • Ataxia​

Neurologic symptoms may occur during or more commonly after CRS symptoms (but rarely before CRS), vary among patients, and have an unclear pathophysiology, distinct from CRS.2

Footnotes

  1. Familial or secondary MAS/HLH.

References

  1. Gödel P, et al. Intensive Care Med. 2018;44(3):371-373.
  2. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25(4):625-638.
  3. Shimabukuro-Vornhagen A, et al. J Immunother Cancer. 2018;6(1):56.
  4. Chavez JC, et al. Hematol Oncol Stem Cell Ther. 2020;13(1):1-6.
  5. Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330.
  6. Doessegger L, Banholzer ML. Clin Transl Immunology. 2015;4(7):e39.
  7. Gutierrez C, et al. Crit Care Med. 2020;48(1):10-21.
  8. Kroschinsky F, et al. Crit Care. 2017;21(1):89.
  9. Schnyder B, Pichler WJ. Mayo Clin Proc. 2009;84(3):268-272.
  10. Morris EC, et al. Nat Rev Immunol. 2022;22(2):85-96.

Grading

CRS Grading Systems

Several grading systems have been developed and utilized over the past decade; however, the latest and more commonly used guidelines are the ASTCT consensus criteria.

ASTCT Consensus Criteria: Grade of CRS Defined by Management Intervention7​

  Grade 1 Grade 2 Grade 3 Grade 4
Fever (≥38°C) Yes Yes Yes Yes
Low blood pressure​ No Yes, treatment needed but no vasopressors required Yes, treatment needed, including vasopressors Yes, aggressive treatment neededa
and/or​
Low oxygen levels No Yes, minimal intervention needed (low flow, ≤6L O2) Yes, moderate intervention needed (high flow, >6L O2)​ Yes, aggressive/​ life-saving intervention neededb

Footnotes

  1. Multiple blood pressure raising therapies (vasopressors) required.
  2. For example, mechanical ventilation.

References

  1. CTCAE v4.03.
  2. Lee DW, et al. Blood. 2014;124(2):188-195.
  3. CTCAE v6.0.
  4. Porter D, et al. J Hematol Oncol. 2018;11(1):35.
  5. Park JH, et al. Clin Infect Dis. 2018;67(4):533-540.
  6. Neelapu SS, et al. Nat Rev Clin Oncol. 2018;15(1):47-62.
  7. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25(4):625-638.

Management

Therapies to Consider for Management of CRS Symptoms Depending on Severity1,2​

Potential symptom treatment (from least to most severe)
  • Corticosteroids
  • Antipyretics, antihistamines, antiemetics, analgesics
  • Hemodynamic support
  • O2 (for hypoxia)
  • Vasopressors (for severe hypotension)
  • Anti-cytokine therapy (for severe or life-threatening CRS)
  • CPAP, mechanical ventilation

Early intervention is key to reducing the severity of CRS3​

Monitoring Strategies for CRS Should Reflect the Severity and Course of the Event2,4​

Clinical monitoring
  • Body temperature
  • Respiratory rate
  • Blood pressure
  • Heart rate
  • O2 levels
  • Neurological exam
Laboratory monitoring
  • Blood counts
  • Electrolytes
  • Kidney and liver function tests
  • Cytokine profile
  • Mild to moderate CRS (Grades 1-2): Monitor daily and taper with improvement
  • Moderate to severe CRS (Grades 3-4): May require ICU until clinically stable

CRS is considered resolved when there is a sustained resolution of fever and no further need for oxygen supplementation or vasopressors​

References

  1. Lee DW, et al. Blood. 2014;124(2):188-195.
  2. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25(4):625-638.
  3. Gardner RA, et al. Blood. 2019;134(24):2149-2158.
  4. Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330.

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TOP

  • AAAAI
    American Academy of Allergy Asthma & Immunology

  • AE
    Adverse event

  • Ang2
    Angiopoietin-2

  • ARR
    Annualized Relapse Rate

  • ART
    Assisted Reproductive Technology

  • ASTCT
    American Society for Transplantation and Cellular Therapy

  • ATG
    Anti-thymocyte globulin

  • CAR
    Chimeric antigen receptor

  • CD3
    Cluster of differentiation 3

  • CD4
    Cluster of differentiation 4

  • CD8
    Cluster of differentiation 8

  • CD19
    Cluster of differentiation 19

  • CD20
    Cluster of differentiation 20

  • CD226
    Cluster of differentiation 226

  • CDC
    Centers for Disease Control and Prevention

  • CI
    Confidence Interval

  • COVID-19
    Coronavirus disease of 2019

  • CPAP
    Continuous positive airway pressure

  • CR
    Complete response

  • CRP
    C-reactive protein

  • CRS
    Cytokine release syndrome

  • CT
    Computed tomography

  • CTCAE
    Common Terminology Criteria for Adverse Events

  • DIC
    Disseminated intravascular coagulation

  • DLBCL
    Diffuse large B-cell lymphoma

  • DMT
    Disease-modifying therapy

  • DMT
    Disease-modifying treatment

  • DoCR
    Duration of complete response

  • DoR
    Duration of response

  • DBPCFC
    Double-blind, placebo-controlled food challenge

  • ECOG PS
    Eastern Cooperative Oncology Group performance status

  • ECTRIMS
    European Committee for Treatment and Research in Multiple Sclerosis

  • EDSS
    Expanded Disability Status Scale

  • EMA
    European Medicines Association

  • FAERS
    FDA Adverse Event Reporting System

  • FDA
    Food and Drug Administration

  • FDA
    US Food and Drug Administration

  • FL
    Follicular lymphoma

  • HCP
    Health Care Provider

  • HGBCL
    High-grade B-cell lymphoma

  • HLH
    Hemophagocytic lymphohistiocytosis

  • ICANS
    Immune effector cell-associated neurotoxicity syndrome

  • ICU
    Intensive care unit

  • Ig
    Immunoglobulin

  • IgE
    Immunoglobulin E

  • IgG1
    Immunoglobulin G1

  • INR
    International normalized ratio

  • IRC
    Independent Review Committee

  • IRR
    Infusion-related reaction

  • ITIM
    Immunoreceptor tyrosine-based inhibitory motif

  • LLN
    Lower limit of normal

  • LMP
    last menstrual cycle

  • LMP
    Last menstrual period

  • MAS
    Macrophage activation syndrome

  • MCA
    Major congenital anomalies

  • MHC
    Major histocompatibility complex

  • MS
    Multiple sclerosis

  • MSKCC
    Memorial Sloan Kettering Cancer Center

  • NK
    Natural killer

  • NO
    Nitric oxide

  • NOS
    Not otherwise specified

  • OB/Gyn
    Obstetrics and Gynecology

  • OCR
    OCREVUS (ocrelizumab)

  • OR
    Odds ratio

  • ORR
    Objective response rate

  • PD-1
    Programmed cell death protein 1

  • PD-L1
    Programmed death-ligand 1

  • PET
    Positron emission tomography

  • PFS
    Progression-free survival

  • PMBCL
    Primary mediastinal B-cell lymphoma

  • PML
    progressive multifocal leukoencephalopathy

  • PPMS
    Primary progressive multiple sclerosis

  • PTT
    Partial thromboplastin time

  • PVR
    Poliovirus receptor

  • RID
    Relative infant dose

  • RMS
    Relapsing multiple sclerosis

  • RRMS
    Relapsing-remitting multiple sclerosis

  • SAE
    Serious adverse event

  • T
    Trimester

  • TCR
    T-cell receptor

  • TIGIT
    T cell immunoreceptor with Ig and ITIM domains

  • UCSF
    University of California San Francisco

  • USPI
    United States Prescribing Information

  • URTI
    Upper respiratory tract infection

  • UTI
    Urinary tract infection

  • VWF
    von Wilebrand factor

  • NIH
    National Institutes of Health