The DOI matches its Crossref record; 161 of the 162 references it cites were found in a registry or an index; none of the 97 sources its claims cite is checked for support yet.
Into the Eye of the Cytokine Storm
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
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In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Cytokine Dynamics
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“IL-1 is a key cytokine driving proinflammatory activity in bronchoalveolar lavage fluid of patients with lung injury (118).”
§ Into the Eye of the Cytokine Storm > Cytokine Storm Pathology
What the sources say
- Not checked yetcites [118] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Cytokine Dynamics
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“The anti-inflammatory cytokine IL-10 appears somewhat later, as the body attempts to control the acute systemic inflammatory response.”
§ Into the Eye of the Cytokine Storm > Cytokine Storm Pathology
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Cytokine Dynamics
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“An experimental study of rabbits with severe Pseudomonas pneumonia and systemic sepsis provided definitive evidence that TNF instilled into the lungs could pass into the systemic circulation, providing direct communication between the lungs and the bloodstream (80).”
§ Into the Eye of the Cytokine Storm > Cytokine Dynamics
What the sources say
- Not checked yetcites [80] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Systemic production of IL-10 following the onset of a cytokine storm is a marker of a counter-anti-inflammatory response that has been termed “immunoparalysis,” in that it is associated with downregulation of neutrophil and monocyte function in the systemic circulation (32,42,49).”
§ Into the Eye of the Cytokine Storm > Cytokine Storm Pathology
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“The intensity of the inflammatory response in the lungs reflects a balance between proinflammatory cytokines (e.g., TNF and IL-1) and their cognate soluble receptors or inhibitors (TNFR1, TNFR2, and IL-1RA), which inhibit the activity of these inflammatory cytokines in the aqueous phase of alveolar fluid (113).”
§ Into the Eye of the Cytokine Storm > Regulation of Pro-and Anti-Inflammatory Cytokines
What the sources say
- Not checked yetcites [113] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“A recent GWAS identified multiple polymorphisms in cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a SOCS family member that controls IL-2 signaling, that were associated with increased susceptibility to bacteremia, tuberculosis, and severe malaria in persons in Gambia, Hong Kong, Kenya, Malawi, and Vietnam (77).”
§ Into the Eye of the Cytokine Storm > Host Susceptibility to the Cytokine Storm
What the sources say
- Not checked yetcites [77] source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It appears that pigs mount a protective proinflammatory response without tipping the scale to promote an adverse cytokine storm.”
§ Into the Eye of the Cytokine Storm > Differential Host Proinflammatory Responses
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Probably not a substantial claim. 16
- It may state two separate claims as one. 38
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Cytokine Storm Pathology
What the sources say
- Not checked yetcites [84]
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Rests on an assumption: Inflammation associated with a cytokine storm begins at a local site and spreads throughout the body via the systemic circulation.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Interleukins.
What the sources say
- Not checked yetcites [124]
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Chemokines.
What the sources say
- Not checked yetcites [49]
- Not checked yetcites [30]
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Cytokine Storm Pathology
What the sources say
- Not checked yetcites [138]
- Not checked yetcites [136] source
- Not checked yetcites [1]
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Regulation of Pro-and Anti-Inflammatory Cytokines
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Studies of patients with severe sepsis due to pulmonary or nonpulmonary infections show characteristic plasma cytokine profiles, which change over time.”
§ Into the Eye of the Cytokine Storm > Cytokine Storm Pathology
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Cytokine Storm Pathology
What the sources say
- Not checked yetcites [121]
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Cytokine Storm Pathology
What the sources say
- Not checked yetcites [1]
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Cytokine Storm Pathology
What the sources say
- Not checked yetcites [104]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Cytokine Gene Expression Kinetics
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Differential Host Proinflammatory Responses
What the sources say
- Not checked yetcites [93]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Key Cytokine Storm Mediators
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Different influenza viruses may present agonists accounting for differential host proinflammatory responses to infection.”
§ Into the Eye of the Cytokine Storm > Differential Host Proinflammatory Responses
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Cytokine Gene Expression Kinetics
What the sources say
- Not checked yetcites [24]
- Not checked yetcites [83]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Host Susceptibility to the Cytokine Storm
What the sources say
- Not checked yetcites [150]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Transcriptional activation of innate immune genes was observed as early as 1 day postinfection and remained sustained through the course of infection.”
§ Into the Eye of the Cytokine Storm > Cytokine Gene Expression Kinetics
What the sources say
- Not checked yetcites [73]
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Differential Host Proinflammatory Responses
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Host Susceptibility to the Cytokine Storm
What the sources say
- Not checked yetcites [55]
- Not checked yetcites [140]
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Differential Host Proinflammatory Responses
What the sources say
- Not checked yetcites [93]
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Cytokine Gene Expression Kinetics
What the sources say
- Not checked yetcites [27]
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Host Susceptibility to the Cytokine Storm
What the sources say
- Not checked yetcites [100]
- Not checked yetcites [101]
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Cytokine Gene Expression Kinetics
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Increased Capillary Permeability Syndrome
What the sources say
- Not checked yetcites [102]
- Not checked yetcites [44]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Another consequence of the cytokine storm in dengue virus infection is an increased capillary permeability syndrome.”
§ Into the Eye of the Cytokine Storm > Increased Capillary Permeability Syndrome
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“One characteristic feature of SARS is the development of pulmonary fibrosis, observed with inflammation and hypercytokinemia.”
§ Into the Eye of the Cytokine Storm > Strength of Chemoattractant Responses
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Despite these efforts, none has been proved to be effective (98), and some have worsened the outcome (19).”
§ Into the Eye of the Cytokine Storm > Challenges of Current Immunotherapies
What the sources say
- Not checked yetcites [98]
- Not checked yetcites [19]
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Conversely, in patients with uncomplicated dengue, relatively more CD8 ϩ T cells display CD107a and few express only IFN-␥ and/or TNF.”
§ Into the Eye of the Cytokine Storm > Increased Capillary Permeability Syndrome
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Increased capillary permeability in dengue usually occurs between days 4 and 6 of illness, is transient, and only occasionally results in hypovolemic shock.”
§ Into the Eye of the Cytokine Storm > Increased Capillary Permeability Syndrome
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Intriguingly, severe dengue occurs most commonly in individuals experiencing a second infection with a serotype distinct from that of a past exposure.”
§ Into the Eye of the Cytokine Storm > Increased Capillary Permeability Syndrome
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Increased Capillary Permeability Syndrome
What the sources say
- Not checked yetcites [86]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Increased Capillary Permeability Syndrome
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“For example, gemfibrozil targets PPAR␣, dampening the inflammatory response and improving the survival of mice infected with influenza H2N2 virus (20).”
§ Into the Eye of the Cytokine Storm > Implications for Therapeutic Strategies
What the sources say
- Not checked yetcites [20]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Strength of Chemoattractant Responses
What the sources say
- Not checked yetcites [21]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Increased Capillary Permeability Syndrome
What the sources say
- Not checked yetcites [134]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Yet to date, successful targeting of the immune system during acute infections has proved to be extraordinarily difficult and largely unsuccessful.”
§ Into the Eye of the Cytokine Storm > TARGETING THE CYTOKINE STORM
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Increased Capillary Permeability Syndrome
What the sources say
- Not checked yetcites [10]
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Strength of Chemoattractant Responses
What the sources say
- Not checked yetcites [158]
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > Implications for Therapeutic Strategies
What the sources say
- Not checked yetcites [147]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Peroxisome proliferator-activated receptors (PPARs) are lipidactivated transcription factors that act as key regulators of lipid metabolism and inflammation (reviewed in reference 12).”
§ Into the Eye of the Cytokine Storm > Implications for Therapeutic Strategies
What the sources say
- Not checked yetcites [12]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Challenges of Current Immunotherapies
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > Challenges of Current Immunotherapies
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
In the paper
“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).”
§ Into the Eye of the Cytokine Storm > TARGETING THE CYTOKINE STORM
What the sources say
- Not checked yetcites [129]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Genomic studies have revealed chemokine gene expression and regulation patterns that can impact Th1-and Th2biased immunopathology.”
§ Into the Eye of the Cytokine Storm > Strength of Chemoattractant Responses
Strength:plain· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > CONCLUDING REMARKS
Strength:plain· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > CONCLUDING REMARKS
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > CONCLUDING REMARKS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > CONCLUDING REMARKS
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Into the Eye of the Cytokine Storm > CONCLUDING REMARKS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We know that individuals respond differently to infection and that individual responses to antibiotics and adjunct therapies also vary (141).”
§ Into the Eye of the Cytokine Storm > Implications for Therapeutic Strategies
What the sources say
- Not checked yetcites [141]
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.”
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?
In the citing paper
“Cytokine storms have been reported in several viral infections [96], including SARS-CoV-2 [9, 97].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [96]
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Metadata
- 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)
- 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
- 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
- bronze
- doi.org
- 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
- Life Sciences › Immunology and Microbiology › Immunology › 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.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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.
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