Cytokine Cascade

An in-depth look at what happens when our immune system turns on us.

The Cytokine Cascade or cytokine storm is a relatively recently described autoimmune response in which the body’s immune system gets caught in a positive feedback loop leading to a runaway and potentially fatal autoimmune response.

A cytokine cascade can be particularly troublesome treat as it is the normal response of a healthy immune system, and so treatment usually focusses on the active interference of the immune processes rather than treatment of the underlying infection.

Cytokine cascades have been implicated in a wide variety of deaths relating to many different conditions, from sepsis, influenza and smallpox, through to Ebola and systemic inflammatory response syndrome1.

The cytokine cascade has been implicated as a contributing factor in the severity of many recent influenza outbreaks, notably the bird flu (H5N1) and swine flu2, as well as the SARS epidemic of 20033. It is believed that a cytokine cascade would explain the unusually high number of deaths from seemly young and healthy individuals.

Clinical Trial Incident

Cytokine cascade was made infamous in the biomedical community when a first-in-man clinical trial of a drug known as TGN1412 caused a severe cytokine cascade in six men4. Although all men eventually survived the ordeal, it forever changed the policies relating to clinical trials of drugs, as well as kick-started more focused research into the cytokine cascade and how best to manage it. While not entirely related to this article, the clinical report of the TGN1412 incident is well worth a read for clinical contexts of the cytokine cascade.


Pathophysiology

Cytokine cascades are a positive feedback loop involving the signalling chemicals, known as cytokines, and immune response cells, in this case, T-cells and macrophages. The cytokines activate these immune response cells and are normally kept in check by various body systems5. In some cases, however, the action of the immune cells may lead to the production of more cytokines, which in turn leads to further activation of more immune cells, which proceed to cause more cytokines, and so on. Without prompt medical intervention, this feedback loop will ultimately prove fatal as the immune system attacks and destroys the body tissues.

The Feedback Loop

T-cells are an active immune response cell that deals with body cells that have been infected by bacteria, viruses, or may have become cancerous. They activate other immune response such as causing inflammation, activating macrophages and signalling other T-cells. it is here that the feedback loop occurs. But first, we must understand how the T-cell is activated to begin with.

A T-cell may be activated inadvertently (a false-positive), by a body cell that may “ask” to be killed, or by an invading organism or infection. Regardless of how the T-cell is activated, once activated, it releases cytokines which signal not only the activation of the inflammatory response and macrophages but also signals other T-Cells that there is a problem. As other T-cells detect the cytokines, it will elicit a dramatic response. These T-cells will begin to divide rapidly into newer T-cells, which in turn release more cytokines, causing the activation and reproduction of more T-cells. While this process is effective in dealing with invasive and infectious organisms, when the regulatory process is interrupted, this immune response can turn against the body and start attacking healthy tissues.

One potential cause is the failure of the regulatory T-cells to signal other immune cells to stand-down through inhibitory cytokines. Another theory suggests that a normal body antibody may be misinterpreted by the T-cells, resulting in an immune response focussed on a healthy tissue.

Regardless of the specifics of how the T-cells are activated, the cytokine cascade is a failure of the immune system to cease an immune response, leading to a runaway positive feedback loop that can be fatal if not halted by medical intervention.

Clinical Presentation

Patients may present with high fever, swelling, redness, extreme fatigue and nausea. It is important to note that some patients may present with what appears to be an aggressive infection, that does not respond to treatment.

Medical Management

Medical interventions generally focus on interfering with the immune response to halt the feedback loop and cease the immune response. This is usually achieved by administering corticosteroids1, TNF-alpha inhibitors6, or with Gemfibrozil, which inhibits the production of pro-inflammatory cytokines, which can halt the reaction7.

Nursing Considerations

The nurse should remain vigilant when caring for any patient with an unknown infection, or otherwise unexplained flu-like symptoms. These conditions can present as initially benign but have the potential to deteriorate rapidly into a life-threatening state. The nurse should also remain vigilant in monitoring patients with confirmed cytokine cascade, and report any changes in the patients condition promptly.

References

1.
Drazen JM, Cecil RL, Goldman L, Bennet CJ. Cecil Textbook of Medicine. 21st ed. W.B. Saunders; 2000.
2.
Haque A, Hober D, Kasper L. Confronting potential influenza A (H5N1) pandemic with better vaccines. Emerg Infect Dis. 2007;13(10):1512-1518. [PubMed]
3.
Huang K, Su I, Theron M, et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. 2005;75(2):185-194. [PubMed]
4.
Vidal J, Kawabata T, Thorpe R, et al. In vitro cytokine release assays for predicting cytokine release syndrome: the current state-of-the-science. Report of a European Medicines Agency Workshop. Cytokine. 2010;51(2):213-215. [PubMed]
5.
Murphy K, Travers P, Walport M. Signalling Through Immune System Receptors. In: Janeway’s Immunology. 7th ed. Garland; 2007:0-0.
6.
Gelinck L, van der, Beyer W, et al. The effect of anti-tumour necrosis factor alpha treatment on the antibody response to influenza vaccination. Ann Rheum Dis. 2008;67(5):713-716. [PubMed]
7.
Budd A, Alleva L, Alsharifi M, et al. Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrob Agents Chemother. 2007;51(8):2965-2968. [PubMed]

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