Cytokine Storms is a complex multicellular inflammatory phenomenon. It is a biological consequence of cytokine overproduction in the human body; it is associated with a variety of infectious and noninfectious diseases. In the most severe cases, it is fatal to the patients. 

What is Cytokine Storm?

The word “Cytokine” is derived from Greek words, cell (for cyto) and movement (for kinos or kinin).

“Cytokine Storm” is an overreaction of the human body’s immune system and it can be fatal to the patient. This overreaction is a severe immune reaction where too many pro-inflammatory cytokines are released into the blood in an uncontrolled manner (2).

What are Cytokines? Which cell types produce them?

Cytokines are specialized proteins; they are typically small in size (kDa) and are secreted or extracellular proteins; their main function is to facilitate cell-to-cell communications and participate in intracellular signaling cascades. A famous cytokine is IL-3 — a growth cytokine involved in a variety of activities such as hematopoietic cell growth, differentiation and apoptosis.

What’s the trigger for Cytokine Storm?

A cytokine storm is trigged by an infection, an autoimmune condition, adoptive T-cell therapies (a type of immunotherapy such as CAR-T therapy), or a disease (such as the systemic inflammatory response syndrome, SIRS). Typical symptoms include high fever, redness/swelling, extreme fatigue and nausea (1-3). Immune cells such as T cells and Macrophages are signaled to migrate to the site(s) of infection. Upon activation, they produce more signaling cytokines for themselves and for recruiting other immune cells. We do not know why this feedback loop can get out of control, which leads to a storm.

Which cell types produce the cytokines? 

B cells, T cells, NK cells, Macrophages, Dendritic cells, and Monocytes. (Sounds like a storm or a hurricane?)

Which cytokines are associated with Cytokine Storm?

Interferons, interleukins, chemokines, colony-stimulating factors (CSFs), and tumor necrosis factor s (TNFs) (1). Both pro-inflammatory and anti-inflammatory cytokines are found in patients experiencing “the storm”. 

For example, activated T cells can release sIL2Rα, IFNγ, IL6, sIL6R, GM-CSF; activated monocytes/macrophages can release IL1RA, IL10, IL6, IP10, MIG, INFα, MIP1α, MIP1β, sIL6R; monocytes/macrophages can release MCP1, MIP1β;  tissue damages sites can release IL8, GCSF, GMCSF, VEGF, IL6, sRAGE. (5-8) In another example of a cytokine storm syndrome, CAR-T therapy can induce the following cytokines: IFNγ, IL10, IL6, IL8, IP10, MCP1, MIP1β, and IL2Rα. GM-CSF is another commonly identified cytokine elevated in a significant number of patients. (5-8)

What has viruses like COVID-19 done to trigger Cytokine Storm?

When the COVID-19 viral particles enter human lung cells (see previous post here), immune cells are summoned to the region to attack the virus. This results in inflammation in the lung. For some patients, inflammation goes into hyper-drive and becomes hyper-inflammation because the immune cells have become hyperactive. Hypercytokinaemia leads to multi-organ failures and is fatal (9). A recent study of 150 patients indicated that mortality is driven by hyperinflammation (9).

References:

1) Tisoncik, J. R., Korth, M. J., Simmons, C. P., Farrar, J., Martin, T. R., & Katze, M. G. (2012). Into the eye of the cytokine storm. Microbiology and molecular biology reviews : MMBR, 76(1), 16–32.

2) Lee DW et al., Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014 Jul 10;124(2):188-95. 

3) Liu, Q., Zhou, Y. & Yang, Z. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol 13, 3–10 (2016).

4) Thevarajan, I., Nguyen, T.H.O., Koutsakos, M. et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat Med 26, 453–455 (2020).

5) Teachey DT, et al. (2016). “Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia”. Cancer Discovery. 6: 664–79. 

6) Tamura K, Kanazawa T, Tsukada S, Kobayashi T, Kawamura M, Morikawa A. Increased serum monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, and interleukin-8 concentrations in hemophagocytic lymphohistiocytosis. Pediatric blood & cancer. 2008;51:662–8.

7) Takada H, Takahata Y, Nomura A, Ohga S, Mizuno Y, Hara T. Increased serum levels of interferon-gamma-inducible protein 10 and monokine induced by gamma interferon in patients with haemophagocytic lymphohistiocytosis. Clin Exp Immunol. 2003;133:448–53. 

8) Osugi Y, Hara J, Tagawa S, Takai K, Hosoi G, Matsuda Y, et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood. 1997;89:4100–3. 

9) Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034.