Cytokine release syndrome refers to the overwhelming release of cytokines by T-cells or other immune effector cells in the absence of immunomodulation, which can result in severe systemic inflammation, coagulopathy, and multiorgan dysfunction 4. Severe manifestation of cytokine release syndrome is also known as cytokine storm 3. While the term cytokine release syndrome is used to describe the iatrogenic cause of massive cytokine release secondary to chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin's lymphoma 4, it can also occur as a result of infection as in severe cases of COVID-19 3,7.
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Epidemiology
Iatrogenic cytokine release syndrome has an incidence of 37% to 93% and varies between different types of chimeric antigen receptor T-cell therapy 2. It shows the first dose effect due to a high tumor burden at the initiation of therapy 5. It is also more common in the pediatric age group 5.
Associations
It is associated with 6
low platelet count
high marrow tumor burden
lymphodepleting chemotherapy
high dose of chimeric antigen receptor T cell therapy
Diagnosis
In a patient receiving chimeric antigen receptor T-cell therapy, a diagnosis of cytokine release syndrome is made after excluding other possible causes with a similar presentation.
American Society for Transplantation and Cellular Therapy (ASTCT) criteria is used in the grading of cytokine release syndrome 1,6.
grade 1: fever in the absence of hypotension or hypoxia
grade 2: fever with hypotension and hypoxia treated using low-flow nasal cannula
grade 3: fever with hypotension treated using vasopressors and hypoxia treated with high-flow nasal cannula, venturi mask, face mask, or non rebreather mask
grade 4: fever with hypotension treated using multiple vasopressors and hypoxia requiring positive pressure ventilation
Clinical presentation
Fever is the first sign of cytokine release syndrome followed by hypotension. It is accompanied by headache, myalgia, rash, nausea, vomiting and similar non-specific symptoms 2.
Other clinical and laboratory abnormalities indicative of massive cytokine release include 5
neutropenia
hypoxia and respiratory distress syndrome
abnormal cardiac rhythm, cardiomyopathy and cardiac failure
acute kidney injury
liver failure
immune effector cell-associated neurotoxicity syndrome (ICANS)
Pathology
The release of cytokines is attributed to lysis of tumor cells and binding of chimeric antigen receptor to its antigen and consequent activation of T cells and other immune cells 5. Cytokines released include interleukin-6,8,10, tumor necrosis factor alpha, and interferon gamma 4. Activation of macrophages and endothelial cells by the released cytokines results in a positive feedback loop with further release of cytokines 5.
Radiographic features
Cytokine release syndrome may manifest as immune effector cell-associated neurotoxicity syndrome (ICANS) showing cerebral edema and other non-specific radiographic features on cranial CT or MRI 6.
Treatment and prognosis
All patients receiving chimeric antigen receptor T-cell therapy need to be monitored for signs of cytokine release syndrome and depending on the grade may require conservative or intensive treatment.
Corticosteroids and tocilizumab are used in the treatment of patients with cytokine release syndrome grade 2 and above along with appropriate management of fever, hypoxia and hypotension 2. Use of empirical antibiotics is also warranted 2.
Differential diagnosis
other conditions present similarly and need to be ruled out including 5
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