II. Mechanism
III. Causes
- Infections
- Acute Graft Versus Host Disease
- Allogeneic Graft with Hematopoietic Stem Cell Transplant
- Original use of term "Cytokine Storm"
- Allogeneic Graft with Hematopoietic Stem Cell Transplant
-
Chemotherapy
- Muromonab-CD3 (OKT3) Infusion
- Original use of term "Cytokine Release Syndrome"
-
Chimeric Antigen Receptor T Cell Therapy (CAR T-Cell Therapy)
- Onset within the first week of Engineered CAR T Cell infusion, and peaks within the first 2 weeks
- CAR T Cells stimulate release of inflammatory Cytokines (e.g. Interleukin 6, Interferon gamma)
- Severity of reaction is higher with greater tumor burden
- Muromonab-CD3 (OKT3) Infusion
IV. Findings: Symptoms and Signs
- Prodrome: Mild Flu-Like Symptoms
- Fatigue
- Malaise
- Low grade fever
- Headache
- Myalgia
- Arthralgia
- Rash
- Later: Vascular Leak and Multi-organ system failure
- High Fever
- Cardiovascular
- Hypotension and shock
- Tachycardia
- Cardiomyopathy with decreased ejection fraction
- Respiratory
- Neurologic
- Altered Level of Consciousness or Confusion
- Word-finding difficulty
- Headaches
- Hallucinations
- Focal Deficits (Aphasia, Hemiparesis, Cranial Nerve palsies)
- Seizures
- Somnolence
V. Labs
- Pancytopenia
-
Acute Kidney Injury
- Increased Serum Creatinine
- Increased hepatic enzymes
- Abnormal Coagulation Factors
- C-Reactive Protein (CRP)
VI. Differential Diagnosis
- Sepsis
- Tumor Lysis Syndrome
- Anaphylaxis or other severe Adverse Drug Reaction
-
Hemophagocytic Lymphohistiocytosis (HLH)
- High fever
- Increased Serum Ferritin
- Increased Serum Triglycerides
-
Macrophage activation syndrome (MAS)
- Patients with CRS-associated HLH display the typical clinical and laboratory findings of HLH/MAS such as high fevers,
VII. Management
- Stabilization and Supportive Care (often Critical Care)
- Cover with culture and broad spectrum Antibiotics to cover Neutropenic Fever until infection is excluded
- Antipyretics
- Intravenous Fluids
- Vasopressors as needed
- Mechanical Ventilation as needed
-
Tocilizumab (IL-6 receptor Antagonist)
- Dosing: 8 mg/kg (up to 800 mg) or for <30 kg, use 12 mg/kg
- Siltuimab is being studied as alternative agent in 2020
- Blockade of of IL-6 decreases production of proinflammatory Cytokines and acute phase reactants
- FDA Approved for several Rheumatologic Conditions and CRS due to CAR T-Cell Therapy
- Experimental use in CRS due to COVID-19
- Adverse effects: Reactivated VZV and Tb, Neutropenia, Thrombocytopenia, increased LFTs, Lipids, GI perforation
-
Corticosteroids
- Indicated in Tocilizumab-resistant CRS or CRES
- Dexamethasone 10-20 mg IV every 6 hours
- Corticosteroids decrease CAR T Cell efficacy (avoid in mild to moderate cases)
VIII. Complications
- Disseminated Intravascular Coagulation
- Acute Respiratory Distress Syndrome (ARDS)
- Multi-System Organ Failure
IX. References
- Kamer and LoVecchio (2020) Crit Dec Emerg Med 34(8): 24
- Jansson and Pallin (2020) Crit Dec Emerg Med 34(4): 19-28
- Fajgenbaum (2020) N Engl J Med 383:2255-73 [PubMed]
- Shimabukuro-Vornhagen (2018) J Immunother Cancer 6: 56 +PMID:29907163 [PubMed]
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Related Studies
Definition (NCI) | A syndrome that occurs after therapeutic infusion of antibodies into the blood and is characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath. It is caused by the release of cytokines from the cells that are targeted by the antibodies. Most patients experience a mild to moderate reaction; however, the reaction may be severe and life-threatening. |
Definition (NCI_CTCAE) | A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by the release of cytokines from the cells. |
Concepts | Disease or Syndrome (T047) |
Italian | Sindrome da rilascio di citochine |
Japanese | サイトカイン放出症候群, サイトカインホウシュツショウコウグン |
Czech | Syndrom uvolňování cytokinů |
English | Cytokine Release Syndrome, Cytokine release syndrome |
Hungarian | Cytokin release syndoma |
Portuguese | Síndrome de liberação de citocinas |
Spanish | Síndrome de liberación de citoquina |
Dutch | cytokinenvrijgavesyndroom |
French | Syndrome de libération de cytokine |
German | Zytokinefreisetzungs-Syndrom |