COVID-19-induced cytokine storm demonstrates the devastating effects of immune dysregulation

The biological process of a cytokine release storm is a generalized inflammatory response to a pathogen (most recently associated with COVID-19 mortality), or a reaction to a cell-therapy treatment or autoimmune disease (such as primary hemophagocytic lymphohistiocytosis, a severe systemic inflammatory syndrome). Described here are the interaction between the triggered driver cells (both adaptive T-cells and antigen-presenting cells) and the important cytokine players involved (including IL-18, TNF,  IL-1b, IFN-gamma, IL-6 and IL-17).

The inflammatory devastation of a cytokine release storm

“Cytokine storm” is an umbrella term including several kinds of immune dysregulation that can lead to multi-organ failure and death. Characterized by systemic inflammation, organ-specific symptoms range from respiratory (acute respiratory distress syndrome or ARDS, pulmonary edema), neurological (confusion, seizures or delirium), renal (kidney disfunction or kidney failure) to liver (elevated liver enzymes, cholestasis, liver failure) and circulatory failure (cytopenia, anemia, endothelial damage). In all cases of cytokine storm there is an elevated level of cytokines and systemic inflammation.

Typically with infectious agents (whether bacterial or viral) there is a transition from an initial innate immune response (starting within hours of infection) to a suppression of this response, carefully balanced between mounting an effective response against the infection and minimizing the amount of collateral damage caused to different body tissues.

In cases of COVID-19, current available data suggest ~5 to ~11% of the severe cases of COVID-19, or about 2% of all COVID-19 infected patients[1] have elevated cytokine levels consistent with a cytokine storm. Another study compared cytokine levels of COVID-19 affected individuals to those infected with severe influenza, and found 4% of the cases of COVID-19-infected individuals had elevated cytokine levels.2

Other triggers of cytokine storm include chimeric antigen receptor T-cell therapy (known as CAR-T therapy), other pathogenic infections in addition to SARS-CoV-2 such as bacterial sepsis, cancer or autoinflammatory disorders such as EBV-associated hemophagocytic lymphohistiocytosis.

Cytokine storm first triggers a set of immune cells

Once triggered, the innate immune cells (monocytes, neutrophils and macrophages along with a host of other cell types such as dendritic cells and natural killer cells) recognize pathogens, release cytokines and ingest (phagocytose) the invading pathogens. Neutrophils, macrophages and NK cells are most often implicated in cytokine storm, producing excessive amounts of cytokines that are its hallmark.

The adaptive immune system, namely helper T-cells (Th1, Th2, Th9 and Th17, along with Cytotoxic T-Lymphocytes) exude cytokines specific to their cell type (for example Th17 produces IL-17, IL-21 and IL-22 targeting and recruiting neutrophils) to mount a specific response. Chemokines are intricately involved in recruiting specific cell types, including IL-8 (also called CXCL8), MCP-1 (CXCL2), MIP-1a (CCL3) and MIP-1b (CCL4).

The cytokines involved comprise a long list, with the main pro-inflammatory molecules including IL-6, IL-1, IL-17, IL-18, IL-33, IFN-g and GM-CSF. Balancing the inflammation response are anti-inflammatory molecules, including IL-10 and IL-1RA and anti-inflammatory cell types including Treg and mesenchymal stem cells.

A generalized cytokine response amplified into an inflammatory cytokine storm

It should be noted that the defining composition and threshold levels of inflammatory molecules in a cytokine storm has not yet been established. However, the list of the component molecules is long: nine interleukins (of which Interleukin-6, Interleukin-18, Interleukin-17 and Interleukin 1beta are key players). Other important cytokines are Tumor Necrosis Factor (TNF) and Interferon gamma (IFNg), as well as the chemokine IP-10 (CXCL10).. There are an additional six cytokines and three plasma proteins that all take part in an interacting network.

The list of nine interleukins, seven chemokines and three plasma proteins, along with their main roles, are listed in Table 1.3

Cytokine, Growth Factor Function
Interleukin 1 (IL-1) proinflammatory, pyrogenic
Interleukin 2 (IL-2) T-cell growth factor
Interleukin 6 (IL-6) proinflammatory, pyrogenic, increase antibody production
Interleukin 9 (IL-9) activation of mast cells
Interleukin 10 (IL-10) anti-inflammatory cytokine, inhibit Th1
Interleukin 12 (IL-12) Activate Th1
Interleukin 17 (IL-17) Neutrophil inflammation
Interleukin 18 (IL-18) Proinflammatory, activation of Th1
Interleukin 33 (IL-33) Proinflammatory, amplification of Th1 Th2 cells
Interferon gamma (IFN-g) Proinflammatory, activation of macrophages
Tumor Necrosis Factor (TFN) pyrogenic, increase vascularization
Granulocyte macrophage colony stimulating factor (GM-CSF) Proinflammatory
Vascular endothelial growth factor (VEGF) Increase vascularization
Chemokines
Interleukin 8 (CXCL8) Recruit neutrophils
MIG (CXCL9) Recruit Th1, NK and plasmacytoid dendritic cells
IP-10 (CXCL10) Recruit macrophages, Th1 and NK cells
MCP-1 (CCL2) Recruit Th2, monocytes, dendritic cells
MIP-1α (CCL3) Recruit macrophages, Th1, NK, dendritic cells, pyrogenic
MIP-1β (CCL4) Recruit macrophages, Th1, NK, dendritic cells
BLC (CXCL13) Recruit B cells, dendritic cells
Plasma Proteins
C reactive protein (CRP) Increases IL-8 and MCP-1
Complement Contributes to tissue damage
Ferritin Primary cell storage of iron

Table 1: List of cytokines, growth factors, chemokines and plasma proteins involved in cytokine storm. Adapted from reference 3.

The inflammatory responses of both innate and adaptive immune components act downstream on important signaling pathways that cause damage to tissues and organs. The four main pathways are MAPK, NF-kB, JAK-STAT3, and mTOR. The trigger (whether a pathogen or a CAR-T cell therapy treatment) may or may not be present; the levels of inflammation due to the cytokines and chemokines form an amplifying loop of cells producing these molecules, and recruiting additional cell types that in turn, produce additional cytokine and chemokine molecules.

Subsequent damage to organs such as the lung, liver and kidney leads to multiorgan failure.

Targeting cytokines and chemokines preceding severe COVID

Given the multifactorial nature of cytokine storms, involving both the innate and adaptive immune systems, any attempt at bringing back homeostasis for this intricate balance of many cell and molecular components poses a formidable challenge. There are several on-market drugs that inhibit specific components, such as anti-TNF (infliximab, trade name Remicade) or anti-Interleukin-6 (siltuximab, trade name Sylvant); these have been used in early attempts to treat cytokine storm but have been shown to be ineffective.4 Targeting the downstream signaling pathways, for example the JAK-STAT3 with JAK inhibitors such as ruxolitinib have also been attempted but were also ineffective.

As is often the case, further research into the drivers and mitigators of the amplification of cytokine signals is needed.

Olink® Target 48 Cytokine is the ideal protein biomarker panel with which to measure 45 cytokines and chemokines simultaneously. See the link below for further information.5

References

  1. RECOVERY Collaborative Group and Landry MJ et al. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020 383(21):2030-2040. doi:10.1056/NEJMoa2022926
  2. Mudd PA and Ellebedy AH et al. Distinct inflammatory profiles distinguish COVID-19 from influenza with limited contributions from cytokine storm. Sci Adv. 2020 6(50):eabe3024. doi:10.1126/sciadv.abe3024
  3. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020 383(23):2255-2273. doi:10.1056/NEJMra2026131
  4. Stone JH and Mansour MK et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 383(24):2333-2344. doi:10.1056/NEJMoa2028836
  5. Olink Target 48 Cytokine Panel product information. https://www.olink.com/products-services/target/48-cytokine-panel/

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