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Immunology and Cell Biology (2007) 85, 271–273; doi:10.1038/sj.icb.7100062

The advent of the cytokine storm

Ian A Clark

Correspondence: , School of Biochemistry and Molecular Biology, Australian National University, Canberra, ACT 0200, Australia. E-mail: ian.clark@anu.edu.au

The term 'cytokine storm' is now used in popular culture as an explanation for the distinctly unpleasant feeling we all sense at the onset of flu. The expression certainly has common currency, with 21 000 Google hits 12 months ago and 55 000 at the time of writing this article. The two-part Special Feature in the January and February issues of Immunology and Cell Biology acknowledges that the sense of this term, with the added complexity of knowing that the mediators involved are also necessary, at lower concentrations, for innate immunity to function, has finally come of age. While the articles on HIV, hepatitis, flaviviruses, tuberculosis, toxoplasmosis, shigellosis, schistosomiasis and visceral leishmaniasis essentially concern local pathological events from these cytokines, those on poxviruses, dengue, influenza and malaria describe variants of the consequences of a systemic response. Salmonella, because of its range of serovars, has a foot in each camp. The interesting omission is sepsis. Research into this condition has never managed to gain a foothold in some countries, despite it being the major cause of death in intensive care units in all first world countries and a part of the cytokine storm literature since 1981.

In 1993 a group in Boston,1 perhaps mindful of the recent Desert Storm war, coined 'cytokine storm' to describe their observations in graft-versus-host disease (GVHD). As we have reviewed,2 the notion that excessive release of pro-inflammatory cytokines causes GVHD pathology already existed. For instance, in 1987, a polyclonal anti-tumour necrosis factor (anti-TNF) antibody was shown to reduce mortality in a mouse model of this condition.3 The term next appeared in 2002 as a description of the disease mechanism in pancreatitis.4 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 19925 and 1997,6 respectively. The role of excessive release of such cytokines in pancreatitis, along with other examples of tissue injury (trauma, burns) causing disease by excessively activating systemic inflammation, is also covered in the review mentioned above.2

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.7 Subsequently, it was applied to variola virus8 and H5N1 influenza.9 Thus, people new to the concept can be forgiven for assuming it began in non-infectious examples of systemic inflammatory disease and was then also seen to apply to diseases caused by infectious agents. In fact it began in infectious disease in 1981, malaria in particular, although it has been argued from the beginning to be also relevant to systemic Gram-negative bacterial infections and its iatrogenic twin, the Jarisch–Herxheimer syndrome.

Although cytokine storm can be a useful lay term, we must expect clinical and pathological dissimilarities in systemic diseases that have this common fundamental origin. Different triggers for cytokines (lipopolysaccharide (LPS), Gram-positive toxins, fungal toxins, glycosylphosphatidylinositol (GPI) or modulation of RIG-1 gene expression) can be expected to generate different ranges, profiles, concentrations and kinetics of cytokine and chemokine generation and release. Different sites (for example, restricted to one or more tissues, or circulating) of release are obvious additional causes for these differences.

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Origins of the concept, in malaria

Like most observations that beget paradigm changes, this one was not being sought when found. As has been reviewed a number of times over the past few decades,10, 11 our group was trying to understand how pretreatment with the Bacillus Calmette-Guérin (BCG) strain of Mycobacterium tuberculosis controlled a subsequent infection with several strains of haemoprotozoa in mice. No antibody was induced, yet parasites were dying in circulating red cells, not after phagocytosis, as BCG protection might predict. The timely publication of the first paper on tumour necrosis factor (TNF),12 allowed us, in collaboration with these New York tumour researchers, to propose, in 1981, the dual roles of TNF and other cytokines in immunity and disease pathogenesis in malaria and sepsis.13, 14 Some 40 key background papers that demonstrate the development of the idea of TNF being much more than a tumour killer are shown in Table 1 of a 2003 review.11 While this was years before access to the tools was made possible by rTNF, the key predictions of the model stood the test of time once they became available.15, 16, 17, 18 The too rapid appearance and clearance of TNF in acute illness is presumably what prevented neutralizing antibody from being clinically useful, since it prevented illness when given before antibiotic treatment in the Jarisch–Herxheimer syndrome.19

Nowadays, when a TNF superfamily of at least 19 members signalling through 29 receptors has been described,20 it warrants recalling that in the 1980s this complexity was not countenanced. Moreover, rTNF was then freely available for laboratory studies from large batches, manufactured in anticipation of its use in treating tumour patients, that proved to be too toxic because of influenza/malaria-like side effects.21, 22 For a while, this gave TNF an artificial prominence in the literature over other similar cytokines, and it was not until 1992 that we were able to acquire recombinant lymphotoxin (courtesy of Bharat Aggarwal) in quantities that allowed studies parallel to those of TNF.23

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Viral diseases

Our group's interest in understanding why malaria and influenza are so clinically similar led us, in 1989, to propose that influenza and other viral diseases (we argued the case for hepatitis B, influenza, dengue and yellow fever), like malaria, have an inflammatory cytokine origin.24 In 1993, the main CDC filovirus group25 was still promoting the idea that increased endothelial cell permeability in filovirus infections was caused directly by viral invasion of these cells and multiplication within them, but, within a few years, they had espoused inflammatory cytokines by demonstrating that the observed increased permeability was instead the consequence of virally-induced TNF from monocytes and macrophages.26 Since then, the literature on the pathogenesis of serious viral infections, including those caused by a hantavirus, Marburg and Ebola viruses, Lassa and Junin viruses, dengue viruses and influenza virus, has become focused almost exclusively on arguments favouring a central role for inflammatory cytokines.

As noted above, the idea also took root for influenza,27 particularly for the more pathogenic strains. For example, good evidence now exists that influenza A virus stimulates the release of TNF from macrophages28, 29 and that the avian influenza virus, H5N1, which is particularly virulent in humans, generates more TNF in human macrophages than do a range of less virulent strains of human influenza.30 The same is true of the ability of H5N1 to induce inflammatory cytokine responses in primary cultures of human alveolar and bronchial epithelial cells.31 In addition, TNF-related apoptosis-inducing ligand (TRAIL) and TNF mRNA are upregulated in human monocyte-derived macrophages infected with H5N1/97 virus,32 and higher levels of inflammatory cytokines and chemokines are associated with a fatal outcome.33 Moreover, a reconstructed version of the strain of influenza virus responsible for massive human mortality in 1918–1919, but not non-virulent constructs or strains, has recently been reported to induce a strong and prolonged pro-inflammatory cytokine response during the fatal infections it causes in mice34 and macaque monkeys.35

The ICB Special Feature contribution on influenza36 has brought our attention to the possibility of any treatment directed against the systemic inflammation that causes illness in this disease also inhibiting the innate response against the virus. This is a valid possibility, as TNF has been shown to exert a powerful in vitro effect against influenza virus in human epithelial cells.37 It is curious, however, that with close to a million patients having received long-term TNF-neutralizing drugs for rheumatoid arthritis or Crohn's disease by 2004,38 and a call being made in that year for alertness to the possibility of hepatitis or HIV exacerbation,39 there seems to be no reports of enhancement of viral diseases as yet, including influenza. In contrast, reports of exacerbation of tuberculosis, and various bacteria (Pneumococcus, Listeria, Salmonella and Staphylococcus) are not uncommon.

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Malaria and toxoplasma

An adequate response to articles on malaria in the ICB Special Feature,40 which contains interesting detailed data on downstream cellular interactions in a mouse malaria model, would be too lengthy for the confines of this article. In summary, I note that the extensive cytokine research on malaria over the past 20 years has neither been acknowledged nor brought into the author's reasoning. In particular, he now seems to have opted out of cytokines as mediators in malaria, instead advocating that GPI acts more directly. As we have noted,41 since malarial GPI was identified by this group as a malarial toxin42 through its capacity to induce pro-inflammatory cytokines, it would have been most remarkable for them to have chanced upon a molecule that induces cytokines, yet mimics their actions in their absence. This contribution also proposes the same role for GPIs of other protozoa, including Toxoplasma gondii. In contrast, the Special Feature contribution dedicated to this parasite43 provides, throughout, a detailed evidence of the roles of inflammatory cytokines in this disease. Moreover, since inhibiting GPI prevents malaria parasites from inducing TNF,44 TNF and other GPI-induced cytokines will be there, in vivo, whenever malarial GPI is released. Thus, should GPI prove to have independent activity, the observed pathology will, at best, arise from both GPI and these cytokines, not from GPI alone.

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Sepsis

Along with malaria, bacterial sepsis was part of what has become the cytokine storm concept from its inception. Although absent from the Special Feature sections of the January and February issues of this journal, the compelling need to understand this condition, the largest cause of death in intensive care units across the world, has generated the most extensive cytokine storm literature. The extent of this body of knowledge demands that all researchers interested in the concept keep sepsis on their reading list, in the reasonable assumption that the vast body of information it continues to generate will grab their interest. This field, including confusions that arose from the retention of the term 'cachectin', is placed in its historic context in a recent review.45

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Retarded acceptance of these concepts

With cytokines, inflammation and diseases increasingly being the theme of scientific conferences, and now the cytokine storm model of understanding the pathology of systemic infectious diseases being the topic of a two-part Special Feature in this journal, the concept finally seems well-entrenched everywhere. Superficially, it is puzzling that it was late in becoming established in some countries, including Australia, where it began in the 1980s. The cause of this phenomenon, generally accepted to bedevil a number of aspects of medical research, was set out clearly in a quite unrelated field several years ago. Explaining why plate tectonics took so long to get accepted in the geology establishment in certain countries over a period when you could not get a job in Cambridge if you did not espouse it, Gordon Macdonald noted:46

"In all science there is a strong 'herd instinct', and interactions occur largely within these herds. They may argue vigorously about details, but they maintain solidarity, or close ranks, when challenged by other herds or individuals. The herd instinct is strengthened greatly if those making funding decisions are members of that herd. Strays do not get funded, and their work, no matter how innovative, is neglected as the herd rumbles on. Herd members will change their views rapidly, however, if the herd leaders change direction. By contrast, if the innovators are not part of the herd it becomes very difficult, or impossible, for them to change the herd's direction".

In the interests of innovation and originality, particularly within the smaller immunology communities, we should no longer regard this 'herd effect' on ideas originated by strays, which we all regularly see in action, with equanimity. It promises to worsen with the policy of funding fewer and larger herds.

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