Table 1.

Diseases under the cytokine storm syndrome umbrella

Cause of CSS	Example	Notable features
Genetic
Familial HLH	Homozygous PRF1 deficiency	Approximately half of familial HLH in North America
Secondary HLH	Dominant-negative STXBP2 mutation	Early-onset; often triggered by viral infection
Autoinflammatory	NLRC4 activating mutation	Associated with colitis
Primary immunodeficiency	X-linked lymphoproliferative disease (XLP1/2)	EBV-induced
Metabolic	Lysinic protein intolerance (SLC7A7 mutation)	Splenomegaly
Systemic illness
Chronic inflammation	MAS in systemic juvenile idiopathic arthritis	Rash, arthritis
Hematologic malignancy	T cell leukemia	Poor outcome
Lymphoproliferative disorder	Multicentric Castleman disease	HHV8 association
Infectious disease
Sepsis and septic shock	bacterial, viral and fungal pathogens	Poor NK cell function
Herpes virus family	Epstein-Barr virus	High mortality
Influenza	H1N1	HLH gene mutations
Hemorrhagic fever virus	Dengue	Extreme hyperferritinemia
SARS-CoV-2	COVID-19-associated ARDS and MIS-C	Severe pneumonia in ARDS; myocarditis in MIS-C
Other associations
CAR-T cell therapy	Cytokine release syndrome	Frequent central nervous system involvement
Immune dysregulation	Pregnancy	Infectious triggers common
Medications	Anti-CD28 monoclonal antibody	Multiple cytokine release

Abbreviations: ARDS, acute respiratory distress syndrome; CAR-T; chimeric antigen receptor T-cell; COVID-19, coronavirus disease of 2019; EBV, Epstein-Barr virus; HHV8, human herpesvirus-8; H1N1, hemagglutinin-1 neuraminidase-1; HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome; MIS-C, multisystem inflammatory syndrome in children; NK, natural killer; NLRC4, NOD-like receptor family CARD domain containing 4; PRF1, perforin-1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SLC7A7, solute carrier family 7 member 7 ; STXBP2, syntaxin binding protein-2.