Table 1.

Overview of major cytokine storm syndromes.

Condition	Age group	Brief description	Associated cytokines	Symptoms and clinical manifestations	References
Castleman disease (CD)	Adult	• Lymphadenitis that occurs due to excessive lymphoproliferation	• IL-6, IL-1β, TNF-α	• “B-cell associated symptoms” • Hypercytokinemia • Hypergammaglobulinemia • Abnormal cellular function, organomegaly	• 24–26
Cytokine release syndrome and immune effector cell associated neurotoxicity syndrome (CRS/ICANS)	Adult and pediatric	• Extreme immune reaction of cytokine storm and neurotoxic events following CAR-T cell therapy	• IL-6, IL-8, IL-10, and IFN-γ	• CRS symptoms include fever, headache, body aches, malaise • Neurological events relate to altered consciousness, motor and cognitive decline, and seizures	• 27, 30
Drug reaction with eosinophilia and systemic symptoms (DRESS)	Adult and pediatric	• Hyperinflammatory immune response of skin rash and eosinophilia that can result from a variety of drugs	• IL-5, IL-10, IL-18, IFN-γ, and TNF-α	• Fever, itching, malaise • Lymphadenopathy, abnormal leukocyte counts, liver and kidney damage, and gastrointestinal problems	• 31, 32
Graft-versus-host disease (GVHD)	Adult and pediatric	• Donor immune cells attack and initiate widespread recipient tissue damage following a stem cell transplant	• IL-1, TNF-α, IL-2, IL-6, IL-10, IL-12, and IL-18	• Initially presents as liver dysfunction, gastrointestinal problems, and skin rash • It can evolve into eye and mouth dryness, obstructive lung disease, and neurological damage	• 33–35
Primary hemophagocytic lymphohistiocytosis (pHLH)	Pediatric	• Abnormal expansion and proliferation of T cells and macrophages results in hypercytokinemia, hemophagocytosis, and multiorgan damage • Pathogenic gene variants	• IL-1, IL-6, IL-10, IL-18, IFN-γ, and TNF-α	• Cytopenias of two or more cell lines and hepatosplenomegaly • Hemophagocytosis • NK dysfunction	• 19, 36, 37
Secondary hemophagocytic lymphohistiocytosis and macrophage activation syndrome (sHLH/MAS)	Adult	• The form of HLH that is more associated with adults • There are multiple possible triggers for this condition that are not directly related to genetics such as pathogens or autoimmune rheumatic conditions	• IL-1, IL-2, IL-6, TNF-α, and IFN-γ,	• This presents similarly to primary hemophagocytic lymphohistiocytosis • Other symptoms can include skin rash, neurological manifestations, pulmonary and renal failure, or cardiac dysfunction	• 38–40
Immune related adverse events (irAEs)	Adult and pediatric	• A variety of autoimmune-like and multiorgan dysfunctions that can occur after usage of immune checkpoint inhibitors	• TNF-α, IL-1, IL-6, IL-12, IL-17, and IL-23	• Drug hypersensitivity of the skin, central and peripheral neurological manifestations, colitis, pneumonitis, and endocrinopathies	• 41–43
Langerhans cell histiocytosis (LCH)	Pediatric	• Abnormal proliferation of myeloid cells that are destined to be antigen-presenting cells • BRAFV600E gene variant has been strongly associated with some confirmed cases	• IL-1, IL-1β, IL-4, IL-8, GM-CSF, TNF-α,	• Widespread bone lesions from infiltrating Langerhans cells and immune cell activation • Skin problems, pulmonary dysfunction, liver and spleen problems, neurodegeneration	• 44–46
Multisystem inflammation syndrome in children (MIS-C)	Pediatric	• Named for the system-wide hyperinflammation and organ dysfunction seen in a small portion of pediatric patients that were infected with SARS-CoV-2 • Unique from adult patients	• IFN-γ, IL-6, IL-10, TNF-α, IL-17, and IL-18	• Pyrexia, gastrointestinal problems, and skin rash • Neurological, respiratory, and cardiovascular problems are akin to that of Kawaski disease	• 47–49
Sepsis and septic shock	Adult and pediatric	• Systemic and hyperinflammatory immune activation that occurs in response to a pathogen that has entered circulation	• TNF-α, IL-1β, IL-6, and IL-8	• Cardiac dysfunction, tissue hypoperfusion, and organ damage • Disruption in the coagulation system	• 50, 51