The term “cytokine storm” calls up vivid images of an immune system gone awry and an inflammatory response flaring out of control (). The term has captured the attention of the public and the scientific community alike and is increasingly being used in both the popular media and the scientific literature. However, while the general concept of an excessive or uncontrolled release of proinflammatory cytokines is well known, an actual definition of what constitutes a cytokine storm is lacking. Furthermore, there is not a good understanding of the molecular events that precipitate a cytokine storm, of the contribution such a “storm” makes to pathogenesis, or of what therapeutic strategies might be used to prevent the storm or quell it once it has started.
Imagery of a cytokine storm.
Although the concept certainly predates the coining of the term, the first use of “cytokine storm” appears to be in an article published in 1993 on graft-versus-host disease (47
). The use of the term in infectious disease research began in early 2000 in reports on cytomegalovirus (6
), Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (70
), group A streptococcus (15
), influenza virus (154
), variola virus (71
), and severe acute respiratory syndrome coronavirus (SARS-CoV) (63
). The term appears to have first been applied in the context of avian H5N1 influenza virus infection in 2005 (155
), after which it began to appear more frequently in the scientific literature. Public interest in “bird flu” also brought the term cytokine storm into the popular media. A recent Google search for cytokine storm yielded 323,000 hits; over 170,000 were within the past year alone.
Cytokine storms are associated with a wide variety of infectious and noninfectious diseases and have even been the unfortunate consequence of attempts at therapeutic intervention (136
). Previous reviews have centered on the advent of the concept (29
) or its role in graft-versus-host disease (46
), multiple sclerosis (89
), pancreatitis (94
), or multiple organ dysfunction syndrome (145
). Though the term was not explicitly stated, recent reviews have addressed potential cellular and molecular mechanisms contributing to the cytokine storm in viral disease (66
), some of which specifically focused on influenza (114
). In this review, we focus on the cytokine storm in the context of infection, with particular emphasis on respiratory viruses. We also highlight how high-throughput genomic methods are revealing new insights into the cytokine storm. These methods are especially useful for obtaining global views of the complex and intertwined molecular events that attend the upregulation of multiple cytokines.
Our goals in this review are to better define the concept of a cytokine storm and the biological consequences of cytokine overproduction. We will also look at the cytokine storm through the lens of genomics, which is revealing the importance of the kinetics of cytokine gene expression and the remarkable degree of redundancy and overlap in cytokine signaling. Finally, we will address evidence for and against the role of the cytokine storm in the pathology of clinical and infectious disease and discuss why it has been so difficult to use knowledge of the cytokine storm and immunomodulatory therapies to improve the clinical outcomes for patients with severe acute infections.