Table 2.

Differential diagnoses for cytokine release syndrome.

Diagnosis	Clinical Pearls to Differentiate from CRS
Infection/Sepsis	Assess for focal symptoms of infection; follow culture and imaging results; treat empirically for infection particularly in neutropenic patients. Often treated with anti-cytokine therapy simultaneously.
Tumor Lysis Syndrome	Monitor laboratory findings: elevated phosphate, uric acid, calcium, and potassium may help differentiate from CRS
Hypersensitivity	Occurs minutes to hour(s) after infusion; and more frequently in patients with >1 CAR T-cell infusion
Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS)	If suspicious, refer to Histiocyte Society guidelines (33) which includes either molecular mutations OR five of the following: fever; splenomegaly; cytopenia affecting at least 2 different cell lines; hypertriglyceridemia; hemophagocytosis in bone marrow, lymph nodes, liver or spleen; low or absent natural killer cells; elevated ferritin; and increased soluble CD25 concentration (i.e., soluble IL-2 receptor)
Pulmonary Embolism	Evaluate by CT angiography; d-dimer often not helpful as it often elevated in patients with malignancy at baseline and coagulopathies can be related to CRS

CRS, cytokine release syndrome; CAR T-cell, chimeric antigen receptor T-cell; CD25, clusters of differentiation 25, IL-2, interleukin 2; CT, computed tomography.