The cytokine storm has captured the attention of the public and the scientific community alike, and while the general notion of an excessive or uncontrolled release of proinflammatory cytokines is well known, the concept of a cytokine storm and the biological consequences of cytokine overproduction are not clearly defined. Cytokine storms are associated with a wide variety of infectious and noninfectious diseases. The term was popularized largely in the context of avian H5N1 influenza virus infection, bringing the term into popular media.
In 1993 a group in Boston, perhaps mindful of the recent Desert Storm war, coined "cytokine storm" to describe their observations in graft-versus-host disease (GVHD). The term next appeared in 2002 as a description of the disease mechanism in pancreatitis. As with GVHD, the idea was older than the aptly descriptive term, with a pro- and an anti-inflammatory cytokine being incriminated in this condition in 1992 and 1997, respectively. The first use of cytokine storm to describe the mechanism of an infectious disease was probably observed a year later, in 2003, in influenza encephalopathy. Subsequently, it was applied to variola virus and H5N1 influenza.
Figure 1. Surface receptors on T cells can cause a cytokine storm when activated by therapeutic monoclonal antibodies (mAbs). TGN1412 can directly cause some cytokine release, as CD28 is expressed on a variety of cells in the normal immune system. TGN1412 is more potent on human T cells than those from monkeys. This is possibly due to human CD28 having three different transmembrane amino acids, which could cause a sustained calcium response within human T cells. Cross-linking of human CD28 may contribute to the formation of an activated immunological synapse (IS) on the surface of T cells, and binding of CD28SA to Fcγ receptors (FcγRs) on endothelial cells and other leukocytes could cause further cytokine release. Activation of CD28 may also cause upregulation of adhesion molecules such as CD11b on the surface of T cells or other cells of the innate immune system, which can then bind to intracellular adhesion molecule 1 (ICAM1) on endothelial cells. T cell–endothelial complexes have the capacity to cause amplified cytokine production and local endothelial damage. Hence, the cytokine storm and neutrophil infiltration could mediate the capillary leak syndrome with resultant multiple organ failure.
Cytokine storm syndromes (CSS) are a group of disorders representing a variety of inflammatory causes. The primary symptoms of a cytokine storm are high fever, swelling and redness, extreme fatigue and nausea. In some cases the immune reaction may be fatal.
When the immune system is fighting pathogens, cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines. Normally, this feedback loop is kept in check by the body. However, in some instances, the reaction becomes uncontrolled, and too many immune cells are activated in a single place. The precise reason for this is not entirely understood but may be caused by an exaggerated response when the immune system encounters a new and highly pathogenic invader. Cytokine storms have potential to do significant damage to body tissues and organs. If a cytokine storm occurs in the lungs, for example, fluids and immune cells such as macrophages may accumulate and eventually block off the airways, potentially resulting in death.
The cytokine storm (hypercytokinemia) is the systemic expression of a healthy and vigorous immune system resulting in the release of more than 150 known inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors). Both pro-inflammatory cytokines (such as Tumor necrosis factor-alpha, Interleukin-1, and Interleukin-6) and anti-inflammatory cytokines (such as interleukin 10 and interleukin 1 receptor antagonist) are elevated in the serum of patients experiencing a cytokine storm.
The clinical presentations of all cytokine storm symptoms (CSS) can be strikingly similar, creating diagnostic uncertainty. However, clinicians should avoid the temptation to treat all CSS equally, because their inciting inflammatory insults vary widely. Failure to identify and address this underlying trigger results in delayed, inoptimal, or potentially harmful consequences.
Drugs for the treatment of cytokine storm can be classified into the following types: OX40 IG, ACE inhibitors and Angiotensin II Receptor Blockers, Corticosteroids, Gemfibrozil, Free radical scavengers, TNF-alpha blockers.
The occurrence of a “cytokine storm” has been suggested as an explanation for the devastating nature of the 1918 influenza pandemic and perhaps H5N1 influenza. Influenza is thought to be one of the rare conditions able to cause a cytokine storm. Cytokine dysregulation is involved in other syndromes with symptoms much like those seen in complicated influenza (e.g., toxic shock syndrome or gram negative sepsis). In these cases the causes are more related to “always on” T-cell activation (stuck accelerator). Whether “always on” activation and thus continuous pro-inflammatory cytokine production, some other kind of cytokine dysregulation, or nothing to do with cytokines happens in influenza is still open to question. The strongest evidence comes from the clinical presentation of virulent influenza cases and the evidence in mice that infection with influenza virus carrying the HA gene from the 1918 virus seems to strongly activate some immune cells to over-produce a half dozen or more cytokines. An animation from The New England Journal article on H5N1 influenza by Mike Osterholm is meant to illustrate how a positive feedback could cause a cytokine storm, but it is only suggestive of one possibility, because we don’t know how a cytokine storm is produced in influenza (if indeed it is).
However, it is reasonable and plausible to say cytokine dysregulation might be involved in some virulent influenza infections. In desperation, clinicians have treated patients with potent anti-inflammatory drugs, usually steriods. There is no evidence that this helps. A “cytokine storm” of a more limited nature is sometimes seen in cancer chemotherapy patients, where it is treated in its earliest stages by iv. benadryl and steroids, with some success. However in these cases, there is no infectious agent involved; even if steroids worked for influenza-induced cytokine storm, they cause a general downshift of the immune system which might allow the virus to run rampant and kill the patient via ordinary viral pneumonia. In ordinary infection-related sepsis, steroids are shown to slightly increase mortality (Crit Care Med. 1995 Aug;23(8):1430–9.) This is but one of the complicating considerations that clinicians will have to navigate during an outbreak. An isolated study showed that in children with central nervous system (brain) symptoms—an early sign of cytokine storm—due to (human, not H5N1) influenza infection, mild and controlled reduction in body core temperature (hypothermia) seems to reduce damage to brain cells as well as reducing the progression to a full-blown cytokine storm and multi-organ failure. (Pediatrics International Volume 42 Issue 2 Page 197 - April 2000.)
In 2003, researchers at Imperial College London tested a drug that interferes with a “survival signal” that keeps activated T-cells working at the site of inflammation during influenza infection in mice. The signal, another cytokine designated OX40, essentially disables the brakes on the T-cell response. By blocking the OX40 receptor on T-cells, researchers were able protect mice from the serious symptoms of virulent flu (paper in J. of Experimental Medicine and reported in New Scientist). The drug, to be made by a company called Xenova Research, was supposed to be in phase I clinical trial in 2004, but we have no further information of its status (additional information solicited for this entry).