CoChat
Sign Up
Cited by 1,940COVID-19 Clinical Research StudiesCytokine Signaling Pathways and InteractionsInflammation biomarkers and pathways

Into the Eye of the Cytokine Storm

Open access
Tisoncik, Jennifer R., Korth, Marcus J., Simmons, Cameron P., Farrar, Jeremy, Martin, Thomas R., Katze, Michael G.·2012·Microbiology and Molecular Biology Reviews
DOI 10.1128/mmbr.05015-11PMC PMC3294426
Open this paper in CoChat — free accountOpen PDF

Abstract

SUMMARY: 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 this review, we focus on the cytokine storm in the context of virus infection, and we highlight how high-throughput genomic methods are revealing the importance of the kinetics of cytokine gene expression and the remarkable degree of redundancy and overlap in cytokine signaling. We also 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.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that “cytokine storm” remains poorly defined despite its broad use, and that severe infections with respiratory viruses such as influenza, SARS-CoV, and dengue can drive overlapping, redundant proinflammatory cytokine networks that contribute to immunopathology. It highlights genomic evidence for cytokine/chemokine kinetics and host genetic variation, but concludes that immunomodulatory therapies have largely failed to improve outcomes in acute severe infections.

Key findings

  • The term “cytokine storm” lacks a precise definition; its first use appears in a 1993 graft-versus-host disease article, infectious-disease use began in early 2000, and it was first applied to avian H5N1 influenza in 2005. A Google search at the time yielded 323,000 hits, over 170,000 within the past year.
  • In severe infection, plasma cytokines follow a sequence: TNF and IL-1β plus chemokines IL-8 and MCP-1 appear early (minutes to hours), IL-6 rises more sustainedly, and IL-10 appears later as a counter-anti-inflammatory response; persistent downregulation of monocyte HLA-DR 3 to 4 days after severe sepsis and cytokine storm is associated with high mortality.
  • Genomic studies show early and sustained innate immune gene activation: a Vietnamese H5N1 case study compared 18 H5N1-infected people with 8 seasonal H1N1-infected people and found elevated MCP-1/CCL2, IP-10/CXCL10, MIG/CXCL9, and IL-8 in those progressing to severe lung injury; macaque H5N1 lung microarray analysis identified 45 significantly differentially expressed cytokine and chemokine genes.
  • Host genetics shape susceptibility: a hyperfunctioning TLR1 variant was linked to increased organ dysfunction and morbidity from Gram-positive bacteremia; TLR4 Asp299Gly occurred at high frequency in Ghanaian children with severe malaria; CISH polymorphisms were associated with bacteremia, tuberculosis, and severe malaria across several populations; and IFN-λ variants were associated with HCV clearance/treatment response.
  • Therapeutic attempts targeting the host response have mostly failed: corticosteroids, aspirin, monoclonal antibodies, anti-cytokine/anti-chemokine agents, plasma exchange, and statins have not been proven effective, and some worsened outcomes. In mice, S1P1-selective agonists protected against lethal pandemic H1N1 without affecting viral replication; gemfibrozil improved survival in H2N2-infected mice; and zanamivir plus celecoxib/mesalazine increased survival in highly pathogenic H5N1-infected mice.

Methods

  • Design: narrative review of cytokine storm in infection, with emphasis on respiratory viruses (influenza, SARS-CoV, dengue) and on high-throughput genomic approaches.
  • Data/sample: no primary dataset or new sample; the paper synthesizes published human clinical studies, animal models (mice, macaques, ferrets, pigs, rabbits), in vitro cell studies, and clinical trial reports.
  • Main analysis: integrates cytokine biology, pathology, host genetics, functional genomics/microarray findings, knockout and transgenic mouse studies, and immunomodulatory drug studies to describe mechanisms and therapeutic challenges.

Limitations

  • The paper states that an actual definition of cytokine storm is lacking, that molecular events precipitating it are poorly understood, and that its contribution to pathogenesis and optimal therapeutic strategies remain unclear.
  • The paper states that most studies rely on intermittent sampling from one compartment, typically peripheral blood, and measure only a few cytokines/chemokines, failing to interrogate the whole immune cascade in tissues; it also notes no agreement on what should be measured or how NGS data should be analyzed, and that interdependent systems are often studied in silos.
  • Evident from the text: this is a narrative review without a systematic search or meta-analysis, it reports no new primary data, and several key mechanistic conclusions derive from animal models that may not fully mimic human disease—the paper itself notes, for example, that no animal models mimic severe dengue in humans.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1128/mmbr.05015-11

Cites

161 of 161 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 97 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Endogenous products such as oxidized phospholipids and matrix breakdown products also drive inflammation through TLR4 and probably other TLRs, providing a mechanism for perpetuating inflammation when microbial products are being cleared from the lungs.

    “endogenous products such as oxidized phospholipids and matrix breakdown products also drive inflammation through TLR4 and probably other TLRs, providing a mechanism for perpetuating inflammation when microbial products are being cleared from the lungs (68,72).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [68] source

      Not checked in the free run.

    • cites [72] source

      Not checked in the free run.

  • Premisecitation

    IL-1β is a key cytokine driving proinflammatory activity in bronchoalveolar lavage fluid of patients with lung injury.

    “IL-1␤ is a key cytokine driving proinflammatory activity in bronchoalveolar lavage fluid of patients with lung injury (118).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] source

      Not checked in the free run.

  • Interpretationcitation

    In severe infections affecting the deep tissues of the respiratory tract, it is probable that the immunological cascade that takes place directly in the deep tissues is crucial to immunopathology rather than what can be measured as a 'spillover' in the peripheral blood.

    “For instance, in severe infections affecting the deep tissues of the respiratory tract (as has been described in avian influenza or severe primary influenza virus infections), it is probable that it is the immunological cascade that takes place directly in the deep tissues that is crucial to immunopathology rather than what can be measured as a “spillover” in the peripheral blood (28,82,128).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [28] source

      Not checked in the free run.

    • cites [82] source

      Not checked in the free run.

    • cites [128] source

      Not checked in the free run.

  • Premisecitation

    The anti-inflammatory cytokine IL-10 appears somewhat later, as the body attempts to control the acute systemic inflammatory response.

    “The anti-inflammatory cytokine IL-10 appears somewhat later, as the body attempts to control the acute systemic inflammatory response.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [138] source

      Not checked in the free run.

    • cites [136] source

      Not checked in the free run.

  • Interpretationreasoning

    In the lungs, the location of the initial infection does not seem to be a determinant of the severity of local and systemic cytokine storms.

    “Interestingly, while the peripheral blood may not provide an accurate picture of the cytokine profiles in a tissue, in the lungs, the location of the initial infection does not seem to be a determinant of the severity of local and systemic cytokine storms.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 16
  • May combine two claims. 38

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The cytokine storm is best exemplified by severe lung infections, in which local inflammation spills over into the systemic circulation, producing systemic sepsis, as defined by persistent hypotension, hyper-or hypothermia, leukocytosis or leukopenia, and often thrombocytopenia.

    “The cytokine storm is best exemplified by severe lung infections, in which local inflammation spills over into the systemic circulation, producing systemic sepsis, as defined by persistent hypotension, hyper-or hypothermia, leukocytosis or leukopenia, and often thrombocytopenia (84).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84]

      Not checked in the free run.

    • Rests on an assumption: Inflammation associated with a cytokine storm begins at a local site and spreads throughout the body via the systemic circulation.

  • May combine two claims.

    Premisecitation

    IL-1 receptor signaling is responsible for acute lung immunopathology but increases the survival of mice infected with influenza virus by enhancing IgM antibody responses and recruiting CD4+ T cells to the site of infection.

    “IL-1 receptor signaling is responsible for acute lung immunopathology but increases the survival of mice infected with influenza virus by enhancing IgM antibody responses and recruiting CD4 ϩ T cells to the site of infection (124).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The use of TNF inhibitors for the treatment of sepsis has not been successful, possibly due to the early release and short circulating half-life of the cytokine.

    “In contrast, the use of TNF inhibitors for the treatment of sepsis has not been successful (49), possibly due to the early release and short circulating half-life of the cytokine (30).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49]

      Not checked in the free run.

    • cites [30]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The acute-response cytokines TNF and IL-1β and the chemotactic cytokines IL-8 and MCP-1 appear in the early minutes to hours after infection, followed by a more sustained increase in IL-6.

    “The acute-response cytokines TNF and IL-1␤ and the chemotactic cytokines IL-8 and MCP-1 appear in the early minutes to hours after infection, followed by a more sustained increase in IL-6.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [138]

      Not checked in the free run.

    • cites [136] source

      Not checked in the free run.

    • cites [1]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    If one or more regulatory mechanisms of lung inflammation are absent or aberrantly regulated, then the outcome may contribute toward a cytokine storm.

    “As the balance of pro-and anti-inflammatory mechanisms is critical to maintaining lung immune homeostasis, it is conceivable that if one or more of these regulatory mechanisms are absent or aberrantly regulated, then the outcome may contribute toward a cytokine storm.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Studies of patients with severe sepsis due to pulmonary or nonpulmonary infections show characteristic plasma cytokine profiles, which change over time.

    “Studies of patients with severe sepsis due to pulmonary or nonpulmonary infections show characteristic plasma cytokine profiles, which change over time.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Acute lung injury (ALI) is a common consequence of a cytokine storm in the lung alveolar environment and systemic circulation and is most commonly associated with suspected or proven infections in the lungs or other organs.

    “Acute lung injury (ALI) is a common consequence of a cytokine storm in the lung alveolar environment and systemic circulation and is most commonly associated with suspected or proven infections in the lungs or other organs (121).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-6 concentrations in peripheral blood have been used to assess the intensity of systemic cytokine responses in patients with sepsis, because IL-6 production is stimulated by TNF and IL-1β, providing an integrated signal of these two early-response cytokines.

    “IL-6 concentrations in peripheral blood have been used to assess the intensity of systemic cytokine responses in patients with sepsis, because IL-6 production is stimulated by TNF and IL-1␤, providing an integrated signal of these two early-response cytokines (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with persistent downregulation of HLA-DR on monocytes 3 to 4 days after the onset of severe sepsis and cytokine storm have a high mortality rate, suggesting a rationale for therapy to reverse immunosuppression under such circumstances.

    “Patients with persistent downregulation of HLA-DR (a marker of immunosuppression) on monocytes 3 to 4 days after the onset of severe sepsis and cytokine storm have a high mortality rate, suggesting a rationale for therapy to reverse immunosuppression under such circumstances (104).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104]

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Direct comparison of transcriptional responses in infected macaque bronchi showed that these viruses induce similar IFN-regulated gene expression patterns, while genes associated with inflammation were significantly differentially regulated by 1918 and H5N1 viruses.

    “Direct comparison of transcriptional responses in infected macaque bronchi showed that these viruses induce similar IFNregulated gene expression patterns, while genes associated with inflammation were significantly differentially regulated by 1918 and H5N1 viruses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Pigs infected with contemporary H1N1 viruses experienced a transient, early increase in immune response concurrent with greater clinical illness, including greater expression of cytokines and chemokines such as TNF, TNFR, CXCL10, IFN-beta, IL-12alpha, and IFN-related signaling molecules.

    “Pigs infected with the contemporary viruses experienced a transient, early increase in immune response concurrent with greater clinical illness.This included greater expression of cytokines and chemokines such as TNF, TNFR, CXCL10, IFN-␤, IL-12␣, and IFNrelated signaling molecules.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study led by Belisle and colleagues, IL-1R and TNFR KO mice infected with the 1918 virus showed a protective role for IL-1alpha, while TNF exerted adverse cytokine storm effects.

    “In a study led by Belisle and colleagues, IL-1R and TNFR KO mice infected with the 1918 virus showed a protective role for IL-1␣, while TNF exerted adverse cytokine storm effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Different influenza viruses may present agonists accounting for differential host proinflammatory responses to infection.

    “Different influenza viruses may present agonists accounting for differential host proinflammatory responses to infection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TNF is not directly induced in respiratory epithelial cells by influenza virus infection but is induced by secondary mediator cascades distinct from the primary effects of the virus.

    “While a range of proinflammatory cytokines are induced in respiratory epithelial cells, TNF is not directly induced in respiratory epithelial cells by influenza virus infection (24) but rather is induced by secondary mediator cascades distinct from the primary effects of the virus (83).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24]

      Not checked in the free run.

    • cites [83]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyper-and hyporesponders to bacterial products are identifiable in the healthy population, which is explainable in part by genetically determined differences in the structure and function of TLR receptors, particularly TLR1.

    “Hyper-and hyporesponders to bacterial products are identifiable in the healthy population, which is explainable in part by genetically determined differences in the structure and function of TLR receptors, particularly TLR1 (150).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transcriptional activation of innate immune genes was observed as early as 1 day postinfection and remained sustained through the course of infection.

    “Transcriptional activation of innate immune genes was observed as early as 1 day postinfection and remained sustained through the course of infection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The upregulation of cytokines associated with the cytokine storm likely varies between pigs and macaques, potentially in the kinetics of PRR stimulation, allowing the pig to serve as a reservoir for influenza viruses with pathogenic potential.

    “The upregulation of these cytokines associated with the cytokine storm likely varies between pigs and macaques, potentially in the kinetics of PRR stimulation, allowing the pig to serve as a reservoir for influenza viruses with pathogenic potential.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several GWAS have also identified variants of IFN-3 that were associated with spontaneous resolution and successful treatment of hepatitis C virus (HCV) infection.

    “Several GWAS have also identified variants of IFN-3 that were associated with spontaneous resolution and successful treatment of hepatitis C virus (HCV) infection (55,140).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55]

      Not checked in the free run.

    • cites [140]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In contrast to lethal influenza virus infection in other animal models, the increased cytokine and chemokine gene expression in pigs resolved and all pigs recovered.

    “In contrast to the case for lethal influenza virus infection in other animal models, the increased cytokine and chemokine gene expression resolved and all pigs recovered.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFN signaling appears to play a critical role in restricting highly pathogenic influenza viruses to the lung microenvironment, as IFNAR deficiency in mice results in dissemination of the 1918 virus to brain and spleen.

    “IFN signaling appears to play a critical role in restricting highly pathogenic influenza viruses to the lung microenvironment, as IFNAR deficiency in mice results in dissemination of the 1918 virus to brain and spleen (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TLR4 Asp299Gly occurred at a high frequency in Ghanaian children with severe malaria, and the polymorphism was also associated with manifestation of malaria during pregnancy in Ghanaian women.

    “For example, TLR4 Asp299Gly occurred at a high frequency in Ghanaian children with severe malaria (100), and the polymorphism was also associated with manifestation of malaria during pregnancy in Ghanaian women (101).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [100]

      Not checked in the free run.

    • cites [101]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These findings suggest that an accelerated or excessive activation of the inflammasome is detrimental rather than protective in macaques infected with 1918 virus and that dysregulation of type I IFN signaling genes may impact regulation of inflammasome activity.

    “These findings suggest that an accelerated or excessive activation of the inflammasome is detrimental rather than protective in macaques infected with 1918 virus and that dysregulation of type I IFN signaling genes may impact regulation of inflammasome activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    T cells are potent contributors of cytokines to the inflammatory milieu in infected tissues and this contributes to vasodilation during the critical phase of dengue illness, although not all studies have found evidence in support of this hypothesis.

    “These and other data (102) suggest that T cells are potent contributors of cytokines to the inflammatory milieu in infected tissues and that this contributes to vasodilation during this critical phase of the illness, although not all studies have found evidence in support of this hypothesis (44).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [102]

      Not checked in the free run.

    • cites [44]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Another consequence of the cytokine storm in dengue virus infection is an increased capillary permeability syndrome.

    “Another consequence of the cytokine storm in dengue virus infection is an increased capillary permeability syndrome.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    One characteristic feature of SARS is the development of pulmonary fibrosis, observed with inflammation and hypercytokinemia.

    “One characteristic feature of SARS is the development of pulmonary fibrosis, observed with inflammation and hypercytokinemia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Despite efforts to target the host response with anti-inflammatory drugs and adjunct approaches in acute severe infections, none has been proved effective, and some have worsened the outcome.

    “Despite these efforts, none has been proved to be effective (98), and some have worsened the outcome (19).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [98]

      Not checked in the free run.

    • cites [19]

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In patients with uncomplicated dengue, relatively more CD8+ T cells display CD107a and few express only IFN-gamma and/or TNF.

    “Conversely, in patients with uncomplicated dengue, relatively more CD8 ϩ T cells display CD107a and few express only IFN-␥ and/or TNF.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Increased capillary permeability in dengue usually occurs between days 4 and 6 of illness, is transient, and only occasionally results in hypovolemic shock.

    “Increased capillary permeability in dengue usually occurs between days 4 and 6 of illness, is transient, and only occasionally results in hypovolemic shock.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Severe dengue occurs most commonly in individuals experiencing a second infection with a serotype distinct from that of a past exposure.

    “Intriguingly, severe dengue occurs most commonly in individuals experiencing a second infection with a serotype distinct from that of a past exposure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    At the stage of increased capillary permeability in dengue, viremia is in steep decline and serum cytokine concentrations of IFN-gamma and IL-10 are at or near their peak levels.

    “At this stage of the illness, viremia is in steep decline and serum cytokine concentrations of IFN-␥ and IL-10 are at or near their peak levels (86).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Most permeability-inducing factors bind to endothelial cell plasma membrane receptors, activate heterotrimeric G proteins, and cause an increase in intracellular Ca2+, resulting in myosin-driven endothelial contraction and opening of tight junctions.

    “Most permeability-inducing factors bind to endothelial cell plasma membrane receptors, activate heterotrimeric G proteins, and cause an increase in intracellular Ca 2ϩ .This results in myosin-driven endothelial contraction and opening of tight junctions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gemfibrozil targets PPARalpha, dampening the inflammatory response and improving the survival of mice infected with influenza H2N2 virus.

    “For example, gemfibrozil targets PPAR␣, dampening the inflammatory response and improving the survival of mice infected with influenza H2N2 virus (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High plasma levels of the IFN-stimulated chemokines CXCL10 and CCL2 were found in SARS patients, and those who died from infection exhibited significantly higher levels of CXCL10 than those who recovered.

    “High plasma levels of the IFNstimulated chemokines CXCL10 and CCL2 were found in infected patients, and those who died from infection exhibited significantly higher levels of CXCL10 than those who recovered.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vivo, plasma levels of free but not total VEGF-A are elevated in severely ill dengue patients at the time of plasma leakage, while VEGFR2 levels are diminished.

    “In vivo, plasma levels of free but not total VEGF-A are elevated in severely ill patients at the time of plasma leakage, while VEGFR2 levels are diminished (134).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    To date, successful targeting of the immune system during acute infections has proved to be extraordinarily difficult and largely unsuccessful.

    “Yet to date, successful targeting of the immune system during acute infections has proved to be extraordinarily difficult and largely unsuccessful.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gene expression analysis of primary human cells infected with dengue virus revealed strong upregulation of CCL8 and CXCL10, and these proteins were increased in infected patients during the febrile period of the disease.

    “Gene expression analysis of primary human cells infected with dengue virus revealed strong upregulation of CCL8 and CXCL10, and these proteins were increased in infected patients during the febrile period of the disease (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microarray profiling showed a skewing toward Th2 responses that was influenced by the absence of STAT1 signaling and likely accounted for the protein deposition in the lungs.

    “In particular, microarray profiling showed a skewing toward Th2 responses that was influenced by the absence of STAT1 signaling and likely accounted for the protein deposition in the lungs (158).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice treated with DNA encoding transforming growth factor beta1, pulmonary eosinophilic responses were inhibited yet susceptibility to Cryptococcus neoformans, influenza virus, and respiratory syncytial virus was increased.

    “This was observed in mice treated with DNA encoding transforming growth factor ␤1 (TGF-␤1), which inhibited pulmonary eosinophilic responses yet increased susceptibility to Cryptococcus neoformans, influenza virus, and respiratory syncytial virus (147).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147]

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Peroxisome proliferator-activated receptors are lipid-activated transcription factors that act as key regulators of lipid metabolism and inflammation.

    “Peroxisome proliferator-activated receptors (PPARs) are lipidactivated transcription factors that act as key regulators of lipid metabolism and inflammation (reviewed in reference 12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12]

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Previous trials of corticosteroids in dengue have involved patients with hypovolemic shock and did not show benefit, though this could have reflected the late timing of therapy.

    “Previous trials of corticosteroids have involved patients with hypovolemic shock and did not show benefit, though this could have reflected the late timing of therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Despite strong evidence of a cytokine storm in many severe acute infections, it has proven difficult to intervene and improve clinical outcomes, for reasons that remain elusive.

    “Nevertheless, despite strong evidence of a cytokine storm in many severe acute infections, it has proven difficult to intervene and improve clinical outcomes, for reasons that remain elusive.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Many acute infections are characterized by a powerful and potentially destructive immune response, and it would seem logical to target this response in order to reduce the self-inflicted damage initiated by the host in response to infection.

    “As we have discussed, many acute infections are characterized by a powerful and potentially destructive immune response, and it would seem logical to target this response in order to reduce the self-inflicted damage initiated by the host in response to infection (129).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Genomic studies have revealed chemokine gene expression and regulation patterns that can impact Th1- and Th2-biased immunopathology.

    “Genomic studies have revealed chemokine gene expression and regulation patterns that can impact Th1-and Th2biased immunopathology.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The world of host and pathogen genetics has been revolutionized in the last decade, and through scale and increasingly sophisticated biostatistical analysis, what associations mean and how they should be interpreted will continue to be developed.

    “The world of host and pathogen genetics has been revolutionized in the last decade, and through scale and increasingly sophisticated biostatistical analysis, what associations mean and how they should be interpreted will continue to be developed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisenone given

    We have split interdependent systems into silos of research such that studies of the immune cascade rarely integrate the pathogen or the host genetic makeup or attempt to interrogate the whole delicate and rapidly changing immune environment.

    “Moreover, we have split interdependent systems into silos of research such that studies of the immune cascade rarely integrate the pathogen or the host genetic makeup or attempt to interrogate the whole delicate and rapidly changing immune environment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Premisenone given

    The development of transcriptional signatures and proteomics to complement host and pathogen genetic studies is providing great steps forward; however, integrated studies need to be standardized with much tighter definitions of the clinical and phenotypic data.

    “The development of transcriptional signatures and proteomics to complement host and pathogen genetic studies is providing great steps forward; however, we need to standardize these integrated studies with much tighter definitions of the clinical and phenotypic data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Next-generation sequencing has unveiled a more comprehensive view of the transcriptome, enabling identification of large and small RNAs, splice isoforms, and novel transcripts from unannotated genes.

    “For example, NGS has unveiled a more comprehensive view of the transcriptome, enabling identification of large and small RNAs, splice isoforms, and novel transcripts from unannotated genes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The need for better methods for NGS data analysis, including RNA-Seq bias correction and improved isoform quantification, is one of the challenges faced with using this technology.

    “Overall, the need for better methods for NGS data analysis, including RNA-Seq bias correction and improved isoform quantification, is just one of the challenges faced with using this technology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Individuals respond differently to infection and individual responses to antibiotics and adjunct therapies also vary.

    “We know that individuals respond differently to infection and that individual responses to antibiotics and adjunct therapies also vary (141).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141]

      Not checked in the free run.

49 of 49

  • The paper relies on this without support.

    An actual definition of what constitutes a cytokine storm is lacking.

    “an actual definition of what constitutes a cytokine storm is lacking”

  • The paper relies on this without support.

    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 or quell it.

    “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.”

  • The paper relies on this without support.

    We still do not understand the complex nature of the immune response and have probably underestimated its dynamic nature during acute infection.

    “We still do not understand the complex nature of the immune response and have probably underestimated its dynamic nature during acute infection.”

  • The paper relies on this without support.

    Inflammation associated with a cytokine storm begins at a local site and spreads throughout the body via the systemic circulation.

    “Inflammation associated with a cytokine storm begins at a local site and spreads throughout the body via the systemic circulation.”

  • The paper relies on this without support.

    TNF is a central cytokine in acute viral diseases, including those caused by influenza virus, dengue virus, and Ebola virus.

    “TNF is now considered a central cytokine in acute viral diseases, including those caused by influenza virus, dengue virus, and Ebola virus.”

  • The paper relies on this without support.

    There are no animal models that mimic the clinical syndrome of severe dengue in humans.

    “There are no animal models that mimic the clinical syndrome of severe dengue in humans, and therefore observational studies of patient cohorts are the main source of understanding the immunopathogenesis of dengue virus infections.”

  • The authors state this as an assumption.

    The host anamnestic immune response mechanistically contributes to the syndrome of increased capillary permeability that characterizes severe dengue.

    “In these so-called heterotypic infections, the host anamnestic immune response is postulated to mechanistically contribute to the syndrome of increased capillary permeability that characterizes severe dengue.”

  • The authors state this as an assumption.

    Increased TLR expression leads to a stage of hyperresponsiveness to TLR agonists.

    “The increased TLR expression is thought to lead to a stage of hyperresponsiveness to TLR agonists.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

1 of the 162 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Tisoncik, J. R., Korth, M. J., Simmons, C. P., Farrar, J., Martin, T. R., & Katze, M. G.
Affiliations
  • Department of Microbiology, University of Washington, Seattle, Washington, USA
  • University of Washington (US)
  • Oxford University Clinical Research Unit (VN)
ORCID
Venue
Microbiology and Molecular Biology Reviews
Publisher
American Society for Microbiology
Published
2012-03
Volume
76
Issue
1
Pages
16-32
ISSN
  • 1092-2172 (ISSN-L)
  • 1098-5557
DOI
10.1128/mmbr.05015-11
PMC
PMC3294426
OpenAlex
W2129239355
Semantic Scholar
435bd4bfc43c8e55b14aac55445390f0f726da0a
Cited by
1,940
References
162
Citations by year
2026: 41 · 2025: 75 · 2024: 110 · 2023: 159 · 2022: 245 · 2021: 427 · 2020: 453 · 2019: 66 · 2018: 90 · 2017: 65 · 2016: 66 · 2015: 43 · 2014: 54 · 2013: 35 · 2012: 10
FWCI
5.83
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Microbiology and Molecular Biology Reviews (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
Funders
  • U.S. Department of Health and Human Services
  • National Institutes of Health (HHSN272200800060C)
  • National Institute on Drug Abuse (P30DA015625)
  • National Institute of Allergy and Infectious Diseases (U54AI081680, P01AI058113, HHSN272200800060C)
  • National Center for Research Resources (P51‐RR00166, R24RR016354, P51RR000166)
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords
cytokine storm, inflammatory cytokines, viral infection, H5N1 avian influenza, immunomodulatory therapy
MeSH terms
Animals, Communicable Diseases, Humans, Signal Transduction, Cytokines, Influenza A Virus, H5N1 Subtype

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review