Unifying Concepts

Clinical Causes of Cytokine Storm

Cytokine storm is an umbrella term encompassing several disorders of immune dysregulation characterized by constitutional symptoms, systemic inflammation, and multiorgan dysfunction that can lead to multiorgan failure if inadequately treated.

Clinical Causes of Cytokine Storm, Pathologic Drivers, and Therapeutic Approaches*

Type of Cytokine Storm and Trigger Cause Pathologic Cellular or Cytokine Driver Common Therapeutic Approaches
CAR T-cell therapy Infusion of CAR T cells Macrophages, CAR T cells, interleukin-6, interleukin-1β Anti–interleukin-6 antibody, glucocorticoids
Blinatumomab Infusion of CD19- and CD3-specific T-cell receptor–engaging antibody Activated T cells, macrophages, interleukin-6 Anti–interleukin-6 antibody, glucocorticoids
Bacterial sepsis Hematogenous bacterial infection Heterogeneous and multifactorial drivers Intravenous antibiotics
EBV-associated HLH EBV infection in patient with genetic susceptibility Interferon-γ, TNF, CD8+ T cells B-cell–depleting therapy, glucocorticoids
HHV-8–associated MCD HHV-8 infection in patient with HIV coinfection, genetic susceptibility, or both Viral interleukin-6, interleukin-6 B-cell–depleting therapy
Covid-19 SARS-CoV-2 infection, potentially in a susceptible person Unknown driver Glucocorticoids
Monogenic and autoimmune
Primary HLH Germline mutation in genes regulating granule-mediated cytotoxicity CD8+ T cells, interferon-γ T-cell inhibition or ablation, interferon-γ inhibitor, glucocorticoids
Secondary HLH, or MAS Viral cause (EBV or CMV), autoimmune disorder (rheumatoid arthritis or adult-onset Still’s disease), or neoplastic disorder in patient with genetic susceptibility (lymphoma) CD8+ T cells, interferon-γ, interleukin-1β, myeloid-cell autoinflammation Treatment of the underlying cause, in addition to T-cell inhibition or ablation, interleukin-1β inhibitor, JAK1 and JAK2 inhibitors, glucocorticoids
Autoinflammatory disorders Germline mutations in genes regulating the innate immune system and inflammasome activation Innate cells, TNF, interleukin-1β Anti-TNF antibody, anti–interleukin-1 antibody
Idiopathic MCD Unknown cause Interleukin-6, activated T cells, mTOR Anti–interleukin-6 antibody, sirolimus, cyclosporine, cytotoxic chemotherapy, glucocorticoids

* CAR denotes chimeric antigen receptor, CMV cytomegalovirus, Covid-19 coronavirus disease 2019, EBV Epstein–Barr virus, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, HLH hemophagocytic lymphohistiocytosis, JAK1 Janus kinase 1, JAK2 Janus kinase 2, MAS macrophage activation syndrome, MCD multicentric Castleman’s disease, mTOR mammalian target of rapamycin, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.




  1. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020 Dec 3;383(23):2255-2273. [Medline]
  2. Canna SW, Cron RQ. Highways to hell: Mechanism-based management of cytokine storm syndromes. J Allergy Clin Immunol. 2020 Nov;146(5):949-959. [Medline]


Created Jul 20, 2021.

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