A cytokine storm is a condition characterized by an uncontrolled and excessive release of inflammatory cytokines. More specifically, it is a physiological reaction observed in humans and animals in which the immune system through the immune response releases pro-inflammatory signaling molecules in large quantities that further activate white blood cells or leukocytes. This further activation results in the additional release of cytokines, thus resulting in a positive feedback loop.
Take note that “cytokine storm” is often loosely interchanged with the medical condition called cytokine release syndrome or CRS. However, despite having similar clinical presentations, the two technically have different specific characteristics. And although both could emerge from infection and non-infectious causes, CRS has recently become more formally associated with immunotherapies centered on T cell engagement.
Cytokine Storm Explained: From Definition and Mechanism to Causes and Clinical Significance
History and Definition
The first reference to “cytokine storm” in the medical literature seems to appear in the 1993 paper by J. L. Ferrara, S. Abhyankar, and D. G. Gilliland. The authors used the term to describe an inflammatory condition called graft-versus-host disease or GvHD following an allogeneic transplant. It specifically occurs when T cells from the donor attack the healthy cells of the patient and cause the release of excessive pro-inflammatory cytokines.
Another paper by I. A Clark noted that the term appeared once again in a 2002 paper discussing another condition called pancreatitis characterized by the inflammation of the pancreas. Another 2003 paper demonstrated the first use of the term as a reference to a reaction to an infection. Recent studies and discourses have liberally used “cytokine storm” in explaining the large death rates involving healthy young adults during the 1918 Spanish Flu Pandemic.
Nevertheless, the term now paints vivid images of an immune system undergoing an overdrive and an inflammatory response flaring out of control. These descriptions represent the simplest definition of a cytokine storm. However, more specifically, the fact remains that a more scientific definition of what constitutes this “storm” is lacking because of premature understanding of the biological and molecular mechanisms of this condition.
Clinical Presentation and Pathophysiology
The clinical features of a cytokine storm are sustained high-grade fever, outward swelling and redness, extreme fatigue, nausea, and vomiting. Others include joint pain or arthralgia, muscle pain or myalgia, and headaches. There are also cases exhibiting degradation in mental faculties through confusion, hallucination, delirium, and aphasia. Understanding these symptoms better requires understanding the underlying pathophysiology.
Of course, the concept predates the coining of the term. The general mechanism behind a cytokine storm centers on the excessive release of pro-inflammatory cytokines that results in the further activation of lymphocytes that, in turn, results in the additional release of inflammatory molecules. A “storm” of cytokines luridly represents the positive feedback loop transpiring at the biomolecular levels of the immune system and the entire body.
It is also important to note that cytokines are signaling molecules responsible for regulating the immune response. Some of them stimulate this response through their pro-inflammation effects. Others slow it down through their anti-inflammatory effects. Pro-inflammatory cytokines signal specific immune cells to travel to the site of an infection or injury. Others also activate these cells to produce more cytokines to mount an effective immune response.
The body has a mechanism for regulating the interaction between the release of pro-inflammatory cytokines and the activation of immune cells. These include the release of anti-inflammatory cytokines, as well as anti-inflammatory steroid hormones such as glucocorticoids and mineralocorticoids. However, in some instances, the immune response becomes uncontrolled, and there is an excess of immune cells activated in a single site.
Underlying Causes of a Cytokine Storm
Despite a fundamental understanding of its pathophysiology, a more detailed and specific reason why a cytokine storm transpires or, more specifically, how and why the immune system goes on an overdrive remains unknown. Still, the expanding literature has identified pro-inflammatory cytokines associated with a cytokine storm. These are under the classes of interferons, interleukins, chemokines, colony-stimulating factors, and tumor necrosis factors.
Other studies suggest that an overactive immune response could occur when an immune system encounters a novel and highly pathogenic invaders. Several cases of H1N1 infection during the 1918 Spanish Flu Pandemic and the SARS-CoV-2 infection during the COVID-19 pandemic support this postulation. Furthermore, the clinical presentation of the Ebola virus disease caused by ebolaviruses demonstrates an aggressive response against an aggressive pathogen.
There is also a simpler but essential conjecture drawn from the analyses of the underlying pathoetiology of cytokine storm: the condition results from the excessive stimulation of pro-inflammatory factors, insufficient regulation of inflammation, or elements of both. There could be an innate or environmentally derived abnormality in the normal functioning of the immune system, as well as the other systems of the body, including the endocrine system.
Abnormalities in the human body could explain why other individuals are more susceptible to developing this condition than others. For example, individuals with conventional immunodeficiencies or those with some form of autoimmune disorders are more vulnerable to demonstrating aggressive and runaway immune response. There could be an underlying innate and genetic explanation behind this condition.
However, cytokine storm has also been observed even in individuals with no innate predispositions. The environmental factors of this condition postulate that infection from specific pathogens or viruses and bacteria or exposure to allergens tend to trigger an exaggerated immune response. Furthermore, medical procedures such as organ transplants, chemotherapy, and other immunosuppressive therapies could alter the regulatory machinery of the immune system.
Effects and Clinical Significance
The immediate effects of a cytokine storm include the aforementioned clinical features characterized by sustained high-grade fever, outward swelling and redness, extreme fatigue, nausea, and vomiting, as well as joint pain, muscle pain, headaches, confusion, hallucination, delirium, and aphasia. However, these effects represent the observable manifestation of the internal havoc caused by an aggressive immune response.
A storm of cytokines and the corresponding overactivation of immune cells essentially damage the tissues and organs of the affected individual. The overactive immune system attacks the cells of the body, thus causing tissue and organ damage. For example, in a respiratory infection that triggers an excessive release of cytokines, acute lung injury is the common consequence, which can progress to a more severe form called acute respiratory distress syndrome.
The same overactive immune response is also one of the theorized reasons behind the severity and possible fatality of the Ebola virus disease. The rapid and efficient replication of ebolaviruses cause systemic infection in the body. Because of this widespread invasion, the immune system releases more cytokines and activates more immune cells as its last-ditch effort to kill the virus and infected cells. The phenomenon results in a cytokine storm.
A cytokine storm fundamentally involves a systemic inflammation. This inflammatory nature has a clinical significance. In diseases due to an infection, controlling inflammation via anti-inflammatory medications could determine patient recovery. Anti-inflammatory and immunosuppressive interventions could resolve the therapeutic safety and efficacy of certain medical procedures that trigger the excessive release of cytokines.
FURTHER READINGS AND REFERENCES
- Canna, S. W., & Behrens, E. M. 2012. “Making Sense of the Cytokine Storm: A Conceptual Framework for Understanding, Diagnosing, and Treating Hemophagocytic Syndromes.” Pediatric Clinics of North America. 59(2): 329–344. DOI: 1016/j.pcl.2012.03.002
- Clark, I. A. 2007. “The Advent of Cytokine Storm.” Immunology & Cell Biology. 85(4): 271-273. DOI: 1038/sj.icb.7100062
- Ferrara, J. L., Abhyankar, S., and Gilliland, D. G. 1993. “Cytokine Storm of Graft-Versus-Host Disease: A Critical Effector Role for Interleukin-1.” Transplantation Proceedings. 25(P.1/2): 1216-1217. PMID: 8442093
- Konsyse. 2020. “Role of Cytokines: Immunomodulating Agents.” Konsyse. Available online
- Shimabukuro-Vornhagen, A., Gödel, P., Subklewe, M., Stemmler, H. J., Schlößer, H. A., Schlaak, M., … von Bergwelt-Baildon, M. S. 2018. “Cytokine Release Syndrome.” Journal for ImmunoTherapy of Cancer. 6(1). DOI: 1186/s40425-018-0343-9
- Tisoncik, J. R., Korth, M. J., Simmons, C. P., Farrar, J., Martin, T. R., and Katze, M. G. 2012. “Into the Eye of the Cytokine Storm.” Microbiology and Molecular Biology Reviews. 76(1): 16–32. DOI: 1128/mmbr.05015-11