CoChat
Sign Up
Cited by 3,196COVID-19 Clinical Research StudiesAutoimmune and Inflammatory Disorders ResearchSepsis Diagnosis and Treatment

Cytokine storm

Open access
Fajgenbaum, David C., June, Carl H.·2020·New England Journal of Medicine
DOI 10.1056/nejmra2026131PMC PMC7727315
Open this paper in CoChat — free accountOpen PDF

Abstract

Cardiac disorders CTCAE Term Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Pericarditis Asymptomatic, ECG or physical findings (e.g., rub) consistent with pericarditis Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, the texture is a papery thin texture.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes a unifying definition of cytokine storm as elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction beyond a normal pathogen response (or cytokine-driven organ dysfunction if no pathogen is present). It synthesizes mechanisms, causes, and treatments across iatrogenic, pathogen-induced, neoplastic/autoimmune/monogenic, and Covid-19-associated cytokine storm.

Key findings

  • The authors propose three criteria for cytokine storm: elevated circulating cytokine levels, acute systemic inflammatory symptoms, and either secondary organ dysfunction due to inflammation beyond that attributable to a normal pathogen response (if a pathogen is present) or any cytokine-driven organ dysfunction (if no pathogen is present). Improvement with cytokine neutralization or antiinflammatory agents further supports the classification.
  • Key cytokines implicated include interferon-γ, interleukin-1, interleukin-6, TNF, and interleukin-18. Interleukin-6 is highly elevated in CAR T-cell therapy–induced cytokine storm and several other cytokine storm disorders; tocilizumab and siltuximab have shown effectiveness in HLH, idiopathic multicentric Castleman’s disease, and CAR T-cell–induced cytokine storm. Emapalumab was recently approved for primary HLH, and anakinra is effective in some forms of cytokine storm.
  • Causes span iatrogenic triggers (CAR T cells, blinatumomab, TGN1412, rituximab, gene therapies, immune checkpoint inhibitors, cardiac-bypass surgery, allogeneic stem-cell transplantation), pathogens (sepsis, EBV/CMV-associated HLH, HHV-8–associated multicentric Castleman’s disease, influenza), monogenic/autoimmune disorders (primary HLH mutations in PRF1, UNC13D, STXBP1, RAB27A, STX11, SH2D1A, XIAP, NLRC4; autoinflammatory diseases), and Covid-19.
  • In Covid-19, elevated cytokines include interleukin-1β, interleukin-6, IP-10, TNF, interferon-γ, MIP1α and MIP1β, and VEGF; higher interleukin-6 levels are strongly associated with shorter survival. Dexamethasone reduces mortality among the most severe cases with elevated CRP and supplemental oxygen requirements, whereas two large randomized controlled trials of anti–interleukin-6 receptor therapies did not show a survival benefit in hospitalized patients with Covid-19.

Methods

  • Narrative review; no primary study design, sample, or statistical analysis is reported. The authors synthesize literature and propose a unifying definition and conceptual framework for staging, assessment, and treatment of cytokine storm.
  • The review discusses pathophysiological features, clinical presentation, management, and iatrogenic, pathogen-induced, neoplasia-induced, monogenic, and Covid-19–associated causes. No systematic search strategy or meta-analysis is described.

Limitations

  • Stated: no single definition of cytokine storm or cytokine release syndrome is widely accepted, and there is disagreement about how these disorders differ from an appropriate inflammatory response; the National Cancer Institute CTCAE definition is too broad, and the American Society for Transplantation and Cellular Therapy definition focuses too specifically on iatrogenic causes.
  • Stated: the authors do not propose a specific threshold for cytokine elevations above normal or recommend specific cytokine panels or particular cytokines that must be elevated, given the lack of available evidence; they call for future systematic assessment by a multidisciplinary consortium.
  • Stated and evident: mechanisms of Covid-19–associated cytokine storm remain unclear, including whether immune hyperactivity or failure to resolve inflammation underlies severe cases; as a narrative review, it provides no primary data, systematic search, or formal risk-of-bias assessment.

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

Integrity signals

Registry

Crossref · 10.1056/nejmra2026131

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 109 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    Although initial drivers may differ, late-stage clinical manifestations of cytokine storm converge and often overlap.

    “Although the initial drivers may differ, late-stage clinical manifestations of cytokine storm converge and often overlap.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Laboratory findings in cytokine storm are variable and influenced by the underlying cause.

    “The laboratory findings in cytokine storm are variable and influenced by the underlying cause.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning
    § Cytokine Storm

    The line between a normal and a dysregulated response to a severe infection is blurry.

    “the line between a normal and a dysregulated response to a severe infection is blurry”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The immune system is expected to recognize foreign invaders, respond proportionally to the pathogen burden, and then return to homeostasis.
  • Premisecitation

    Levels of serum cytokines - most prominently interferon-γ - are often more elevated in patients with cytokine storm due to CAR T-cell therapy than in patients with sepsis-induced cytokine storm.

    “Levels of serum cytokines — most prominently, interferon-γ — are often more elevated in patients with cytokine storm due to CAR T-cell therapy than in patients with sepsis-induced cytokine storm”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Diorio C, Shaw PA, Pequignot E, et al. Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children. Blood Adv 2020; 4: 5174- 5183. 33095872 PMC7594400 source

      Not checked in the free run.

  • Premisecitation

    Neurologic toxic effects associated with T-cell immunotherapy are often delayed, developing several days after the onset of cytokine storm.

    “The neurologic toxic effects are often delayed, developing several days after the onset of the cytokine storm.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019; 25: 625- 638. 30592986 PMC12180426 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 52
  • May combine two claims. 59

  • Classified as probably not a substantial claim.

    Interpretationnone given
    § Cytokine Storm

    Certain cytokines may be both helpful in controlling an infection and harmful to the host.

    “certain cytokines may be both helpful in controlling an infection and harmful to the host”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Many patients with cytokine storm have hypertriglyceridemia and various blood-count abnormalities, such as leukocytosis, leukopenia, anemia, thrombocytopenia, and elevated ferritin and d-dimer levels.

    “Many patients have hypertriglyceridemia and various blood-count abnormalities, such as leukocytosis, leukopenia, anemia, thrombocytopenia, and elevated ferritin and d-dimer levels.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Symptoms of cytokine storm may be due directly to cytokine-induced tissue damage or acute-phase physiological changes or may result from immune-cell-mediated responses.

    “These symptoms may be due directly to cytokine-induced tissue damage or acute-phase physiological changes or may result from immune-cell–mediated responses.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning
    § Cytokine Storm

    No single definition of cytokine storm or the cytokine release syndrome is widely accepted.

    “No single definition of cytokine storm or the cytokine release syndrome is widely accepted”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In severe cases of cytokine storm, renal failure, acute liver injury or cholestasis, and a stress-related or takotsubo-like cardiomyopathy can develop.

    “In severe cases of cytokine storm, renal failure, acute liver injury or cholestasis, and a stress-related or takotsubo-like cardiomyopathy can also develop.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of takotsubo (stress) cardiomyopathy. N Engl J Med 2015; 373: 929- 938. 26332547 source

      Not checked in the free run.

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

    Interpretationreasoning

    CAR T-cell therapy and other noninfectious causes of cytokine storm can also occur with infections, and infections can develop during the course of therapy, so continued monitoring for infections is warranted.

    “CAR T-cell therapy and other noninfectious causes can also occur with infections, and infections can develop during the course of therapy, so continued monitoring for infections is warranted.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Cytokine storm is an umbrella term encompassing several disorders of immune dysregulation characterized by constitutional symptoms, systemic inflammation, and multiorgan dysfunction that can lead to multiorgan failure if inadequately treated.

    “Cytokine storm is an umbrella term encompassing several disorders of immune dysregulation characterized by constitutional symptoms, systemic inflammation, and multiorgan dysfunction that can lead to multiorgan failure if inadequately treated”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation
    § Cytokine Storm

    The National Cancer Institute's CTCAE-based definition of cytokine storm is too broad, since the criteria for an inflammatory syndrome can also apply to other physiological states.

    “The National Cancer Institute’s definition, based on the Common Terminology Criteria for Adverse Events (CTCAE), is too broad, since the criteria for an inflammatory syndrome can also apply to other physiological states”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019; 25: 625- 638. 30592986 PMC12180426 source

      Not checked in the free run.

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

    Interpretationnone given

    Changes in circulating cell counts in cytokine storm are most likely due to a complex interplay among cytokine-induced changes in production and mobilization of cells from the bone marrow, immune-mediated destruction, and chemokine-induced migration.

    “Changes in circulating cell counts are most likely due to a complex interplay among cytokine-induced changes in production and mobilization of cells from the bone marrow, immune-mediated destruction, and chemokine-induced migration.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The combination of hyperinflammation, coagulopathy, and low platelet counts places patients with cytokine storm at high risk for spontaneous hemorrhage.

    “The combination of hyperinflammation, coagulopathy, and low platelet counts places patients with cytokine storm at high risk for spontaneous hemorrhage.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation
    § Cytokine Storm

    The American Society for Transplantation and Cellular Therapy definition of cytokine storm is based on criteria that focus too specifically on iatrogenic causes of cytokine storm alone.

    “the definition of the American Society for Transplantation and Cellular Therapy is based on criteria that focus too specifically on iatrogenic causes of cytokine storm alone”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019; 25: 625- 638. 30592986 PMC12180426 source

      Not checked in the free run.

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

    Premisereasoning
    § Cytokine Storm

    There is disagreement about how cytokine storm and cytokine release syndrome differ from an appropriate inflammatory response.

    “there is disagreement about how these disorders differ from an appropriate inflammatory response”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nonspecific markers of inflammation such as C-reactive protein (CRP) are universally elevated in cytokine storm and correlate with severity.

    “Nonspecific markers of inflammation such as C-reactive protein (CRP) are universally elevated and correlate with severity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124: 188- 195. 24876563 PMC4093680 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Patients with cytokine storm may have fatigue, anorexia, headache, rash, diarrhea, arthralgia, myalgia, and neuropsychiatric findings.

    “patients may have fatigue, anorexia, headache, rash, diarrhea, arthralgia, myalgia, and neuropsychiatric findings”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Disorders that should be ruled out in considering cytokine storm include anaphylaxis and physiological responses to microbial infections.

    “Disorders that should be ruled out in considering cytokine storm include anaphylaxis and physiological responses to microbial infections.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Cases of cytokine storm can progress rapidly to disseminated intravascular coagulation with either vascular occlusion or catastrophic hemorrhages, dyspnea, hypoxemia, hypotension, hemostatic imbalance, vasodilatory shock, and death.

    “Cases can progress rapidly to disseminated intravascular coagulation with either vascular occlusion or catastrophic hemorrhages, dyspnea, hypoxemia, hypotension, hemostatic imbalance, vasodilatory shock, and death.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Fever in cytokine storm may be high grade in severe cases.

    “the fever may be high grade in severe cases”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368: 1509- 1518. 23527958 PMC4058440 source

      Not checked in the free run.

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

    Premisenone given
    § Cytokine Storm

    Cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders.

    “Cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Many patients with cytokine storm have respiratory symptoms, including cough and tachypnea, that can progress to acute respiratory distress syndrome (ARDS), with hypoxemia that may require mechanical ventilation.

    “Many patients have respiratory symptoms, including cough and tachypnea, that can progress to acute respiratory distress syndrome (ARDS), with hypoxemia that may require mechanical ventilation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Interferon-γ can induce hemophagocytosis by macrophages, and this may contribute to the cytopenias commonly observed in patients with cytokine storm.

    “Interferon-γ can induce hemophagocytosis by macrophages, and this may contribute to the cytopenias commonly observed in patients with cytokine storm.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Zoller EE, Lykens JE, Terrell CE, et al. Hemophagocytosis causes a consumptive anemia of inflammation. J Exp Med 2011; 208: 1203- 1214. 21624938 PMC3173248 source

      Not checked in the free run.

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

    Interpretationreasoning

    Similarly high levels of cytokines in cancer-associated HLH or idiopathic multicentric Castleman's disease would be considered a pathologic state of cytokine storm because no pathogen requiring an immune response is involved and patients benefit from treatment with cytokine neutralization and other antiinflammatory agents.

    “whereas similarly high levels of cytokines in cancer-associated HLH or idiopathic multicentric Castleman’s disease would be considered a pathologic state of cytokine storm because no pathogen requiring an immune response is involved and patients benefit from treatment with cytokine neutralization and other antiinflammatory agents.”
    Quote in the paperSubstantial claim

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

    Premisereasoning

    At increased levels, cytokines can have systemic effects and cause collateral damage to vital organ systems.

    “At increased levels, cytokines can have systemic effects and cause collateral damage to vital organ systems.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Th17 cells have a major role in host defense, particularly antifungal protection, and abnormal Th17-cell function can lead to autoimmunity.

    “Th17 cells have a major role in host defense, particularly antifungal protection, and abnormal Th17-cell function can lead to autoimmunity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol 2009; 27: 485- 517. 19132915 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Lack of a treatment response does not necessarily rule out cytokine storm, because underlying conditions are likely to play a part, a different cytokine may be the disease driver, or the timing of treatment may have been poor.

    “However, lack of a treatment response does not necessarily rule out cytokine storm, because underlying conditions are likely to play a part, a different cytokine may be the disease driver, or the timing of treatment may have been poor.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Excess interleukin-6 may mediate the impairment in NK-cell function by lowering perforin and granzyme production.

    “Excess interleukin-6 may mediate the impairment in NK-cell function by lowering perforin and granzyme production.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Regulatory cell types, decoy receptors for proinflammatory cytokines such as IL1RA, and antiinflammatory cytokines such as interleukin-10 are important for antagonizing inflammatory-cell populations and preventing immune hyperactivity.

    “Regulatory cell types, decoy receptors for proinflammatory cytokines such as IL1RA, and antiinflammatory cytokines such as interleukin-10 are important for antagonizing inflammatory-cell populations and preventing immune hyperactivity.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Neutrophils can produce neutrophil extracellular traps, a network of fibers that contribute to thrombi formation and amplify cytokine production during cytokine storm.

    “Neutrophils can produce neutrophil extracellular traps, a network of fibers that contribute to thrombi formation and amplify cytokine production during cytokine storm.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Cytokines play a key role in coordinating antimicrobial effector cells and providing regulatory signals that direct, amplify, and resolve the immune response.

    “Cytokines play a key role in coordinating antimicrobial effector cells and providing regulatory signals that direct, amplify, and resolve the immune response.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Immune hyperactivation in cytokine storm can occur as a result of an inappropriate or ineffective amplitude of response, involving excessive effector immune-cell activation, an overwhelming pathogen burden, or uncontrolled infections and prolonged immune activation.

    “an inappropriate or ineffective amplitude of response, involving excessive effector immune-cell activation (e.g., in cytokine storm due to CAR T-cell therapy), an overwhelming pathogen burden (e.g., in sepsis), or uncontrolled infections and prolonged immune activation”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    For grading of cytokine storm due to other causes, the immune systems disorders section of CTCAE is used.

    “For the grading of cytokine storm due to other causes, the immune systems disorders section of CTCAE is used”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    HScore and MS score are used for classifying HLH-associated cytokine storm, and HLH-2004 guides treatment.

    “HScore and MS score are used for classifying HLH-associated cytokine storm, and HLH-2004 guides treatment.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Circulating cytokine levels can be difficult to measure because cytokines have short half-lives, circulating levels may not accurately reflect local tissue levels, and measurements may not be easily obtained worldwide.

    “Circulating cytokine levels can be difficult to measure because cytokines have short half-lives, circulating levels may not accurately reflect local tissue levels, and measurements may not be easily obtained worldwide.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Cytokines have short half-lives, which normally prevents them from having effects outside lymphoid tissue and sites of inflammation.

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

    Premisenone given

    Inflammation involves a set of biologic mechanisms that evolved in multicellular organisms to contain invasive pathogens and resolve injuries by activating innate and adaptive immune responses.

    “Inflammation involves a set of biologic mechanisms that evolved in multicellular organisms to contain invasive pathogens and resolve injuries by activating innate and adaptive immune responses.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Cytokine storm involves an immune response that causes collateral damage, which may be greater than the immediate benefit of the immune response.

    “In short, cytokine storm involves an immune response that causes collateral damage, which may be greater than the immediate benefit of the immune response.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The immune system is expected to recognize foreign invaders, respond proportionally to the pathogen burden, and then return to homeostasis.

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

    Interpretationnone given

    Improvement in outcomes with cytokine neutralization or antiinflammatory agents further supports the pathologic role of excessive cytokines and the classification of a condition as a cytokine storm.

    “Improvement in outcomes with cytokine neutralization or antiinflammatory agents further supports the pathologic role of excessive cytokines and the classification of a condition as a cytokine storm.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Th1 cells produce large quantities of interferon-γ, induce delayed hypersensitivity reactions, activate macrophages, and are essential for defense against intracellular pathogens.

    “Th1 cells produce large quantities of interferon-γ, induce delayed hypersensitivity reactions, activate macrophages, and are essential for defense against intracellular pathogens.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989; 7: 145- 173. 2523712 source

      Not checked in the free run.

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

    Interpretationreasoning

    This response requires a balance between sufficient cytokine production to eliminate the pathogen and avoidance of a hyperinflammatory response in which an overabundance of cytokines causes clinically significant collateral damage.

    “This response requires a balance between sufficient cytokine production to eliminate the pathogen and avoidance of a hyperinflammatory response in which an overabundance of cytokines causes clinically significant collateral damage.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The immune system is expected to recognize foreign invaders, respond proportionally to the pathogen burden, and then return to homeostasis.

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

    Interpretationnone given

    Although typically considered to be pathologic, sustained production of cytokines that leads to elevated circulating levels may be necessary to appropriately control some disseminated infections.

    “Although typically considered to be pathologic, sustained production of cytokines that leads to elevated circulating levels may be necessary to appropriately control some disseminated infections.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    In many forms of cytokine storm, macrophages become activated and secrete excessive amounts of cytokines, ultimately causing severe tissue damage that can lead to organ failure.

    “In many forms of cytokine storm, macrophages become activated and secrete excessive amounts of cytokines, ultimately causing severe tissue damage that can lead to organ failure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The cytolytic function of NK cells is diminished in some forms of cytokine storm, which can lead to prolonged antigenic stimulation and difficulty resolving inflammation.

    “The cytolytic function of NK cells is diminished in some forms of cytokine storm, which can lead to prolonged antigenic stimulation and difficulty resolving inflammation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Perez N, Virelizier J-L, Arenzana-Seisdedos F, Fischer A, Griscelli C. Impaired natural killer activity in lymphohistiocytosis syndrome. J Pediatr 1984; 104: 569- 573. 6368780 source

      Not checked in the free run.

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

    Premisenone given

    Interleukin-1 is encoded by two genes (IL1A and IL1B), both of which bind to the same interleukin-1 receptor, activating a cascade of intracellular signaling pathways, including nuclear factor κB (NF-κB).

    “Interleukin-1 is encoded by two genes (IL1A and IL1B), both of which bind to the same interleukin-1 receptor, activating a cascade of intracellular signaling pathways, including nuclear factor κB (NF-κB).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The interleukin-1-receptor antagonist anakinra is effective as a single agent and in combination with other agents for the treatment of some forms of cytokine storm.

    “The interleukin-1–receptor antagonist anakinra is effective as a single agent and in combination with other agents for the treatment of some forms of cytokine storm.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Eloseily EM, Weiser P, Crayne CB, et al. Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 2020; 72: 326- 334. 31513353 source

      Not checked in the free run.

    • cites [34] Durand M, Troyanov Y, Laflamme P, Gregoire G. Macrophage activation syndrome treated with anakinra. J Rheumatol 2010; 37: 879- 880. 20360206 source

      Not checked in the free run.

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

    Premisenone given

    Interleukin-6 is produced by and acts on immune and nonimmune cells across multiple organ systems.

    “Interleukin-6 is one of the more complex cytokines, since it is produced by and acts on immune and nonimmune cells across multiple organ systems.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Interferon-γ, interleukin-1, interleukin-6, TNF, and interleukin-18 are key cytokines that often have elevated levels in cytokine storm and are thought to have central immunopathologic roles.

    “Interferon-γ, interleukin-1, interleukin-6, TNF, and interleukin-18 are key cytokines that often have elevated levels in cytokine storm and are thought to have central immunopathologic roles.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Interferon-γ is primarily secreted by activated T cells and NK cells and is a potent activator of macrophages.

    “Interferon-γ is primarily secreted by activated T cells and NK cells and is a potent activator of macrophages.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Membrane-bound gp130 is ubiquitously expressed, whereas expression of membrane-bound interleukin-6R is restricted largely to immune cells.

    “Membrane-bound gp130 is ubiquitously expressed, whereas expression of membrane-bound interleukin-6R is restricted largely to immune cells.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    B cells are not often associated with the pathogenesis of cytokine storm.

    “B cells are not often associated with the pathogenesis of cytokine storm.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Emapalumab, a monoclonal antibody that binds interferon-γ, was recently approved for the treatment of cytokine storm in patients with primary HLH.

    “Emapalumab, a monoclonal antibody that binds interferon-γ, was recently approved for the treatment of cytokine storm in patients with primary HLH.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med 2020; 382: 1811- 1822. 32374962 source

      Not checked in the free run.

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

    Premisenone given

    Fever, a clinical hallmark of cytokine storm, can be elicited by interleukin-1, interleukin-6, or TNF through distinct mechanisms.

    “Fever, a clinical hallmark of cytokine storm, can be elicited by interleukin-1, interleukin-6, or TNF through distinct mechanisms.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The specific immune cells that secrete the various cytokines are not fully understood and most likely vary among cytokine storm disorders.

    “The specific immune cells that secrete the various cytokines are not fully understood and most likely vary among cytokine storm disorders.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Clinically, interferon-γ causes fever, chills, headache, dizziness, and fatigue.

    “Clinically, interferon-γ causes fever, chills, headache, dizziness, and fatigue.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Vadhan-Raj S, Nathan CF, Sherwin SA, Oettgen HF, Krown SE. Phase I trial of recombinant interferon gamma by 1-hour i.v. infusion. Cancer Treat Rep 1986; 70: 609- 614. 3085930

      Not checked in the free run.

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

    Premisereasoning

    In cis signaling, soluble interleukin-6 binds to membrane-bound interleukin-6R, forming an interleukin-6-interleukin-6R complex that binds to gp130, which then initiates signaling through its intracellular domain.

    “In cis signaling, soluble interleukin-6 binds to membrane-bound interleukin-6R, forming an interleukin-6–interleukin-6R complex that binds to gp130, which then initiates signaling through its intracellular domain.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Interleukin-6 can signal through two main pathways, referred to as classic cis signaling and trans signaling.

    “It can signal through two main pathways, referred to as classic cis signaling and trans signaling.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity 2019; 50: 1007- 1023. 30995492 source

      Not checked in the free run.

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

    Premisenone given

    The membrane-bound interleukin-6R does not possess intracellular signaling domains but signals instead through interaction with membrane-bound gp130.

    “The membrane-bound interleukin-6R does not possess intracellular signaling domains but signals instead through interaction with membrane-bound gp130.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Emapalumab may also be useful in other cytokine storm disorders, such as macrophage activation syndrome or CAR T-cell-associated cytokine storm, although in the latter case, it may diminish antitumor effects.

    “This agent may also be useful in other cytokine storm disorders, such as macrophage activation syndrome or CAR T-cell–associated cytokine storm, although in the latter case, it may diminish antitumor effects.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    In addition to inducing fever, augmenting systemic inflammation, and activating antimicrobial responses such as interleukin-6, TNF can induce cellular apoptosis and regulate immunity.

    “In addition to inducing fever, augmenting systemic inflammation, and activating antimicrobial responses such as interleukin-6, TNF can induce cellular apoptosis and regulate immunity.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The interleukin-18 receptor is constitutively expressed on NK cells and induced on activation in most T cells.

    “The interleukin-18 receptor is constitutively expressed on NK cells and induced on activation in most T cells.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    TNF and other cytokines in the TNF-TNF receptor superfamily are potent inducers of NF-κB, leading to the expression of multiple proinflammatory genes.

    “TNF and other cytokines in the TNF–TNF receptor superfamily are potent inducers of NF-κB, leading to the expression of multiple proinflammatory genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    This trans signaling results in systemic hyperinflammation involving secretion of MCP-1, interleukin-8, and additional interleukin-6, as well as increased VEGF and reduced E-cadherin expression on endothelial cells, which contribute to vascular hyperpermeability, leakiness, hypotension, and pulmonary dysfunction.

    “This results in systemic hyperinflammation involving secretion of monocyte chemoattractant protein 1 (MCP-1), interleukin-8, and additional interleukin-6, as well as increased vascular endothelial growth factor (VEGF) and reduced E-cadherin expression on endothelial cells, which contribute to vascular hyperpermeability, leakiness, hypotension, and pulmonary dysfunction.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity 2019; 50: 1007- 1023. 30995492 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The effectiveness of anti-TNF therapies in certain autoinflammatory-driven cytokine storm conditions points to their potential role in the treatment of cytokine storm, but the limitations and dangers of anti-TNF therapies in patients with sepsis indicate that more work is needed.

    “The effectiveness of anti-TNF therapies in certain autoinflammatory-driven cytokine storm conditions points to their potential role in the treatment of cytokine storm, but the limitations and dangers of anti-TNF therapies in patients with sepsis indicate that more work is needed.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The inflammasome is a multimolecular cytosolic sensor that detects pathogenic microorganisms and sterile stressors and activates caspase-1 during the process of pyroptosis, which, in turn, causes the inactive precursor forms of interleukin-1β and interleukin-18 to become the active forms.

    “The inflammasome is a multimolecular cytosolic sensor that detects pathogenic microorganisms and sterile stressors and activates caspase-1 during the process of pyroptosis, which, in turn, causes the inactive precursor forms of interleukin-1β and interleukin-18 to become the active forms.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237- 241. 16407889 source

      Not checked in the free run.

    • cites [42] Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ 2019; 26: 99- 114. 30341423 PMC6294779 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interleukin-18 is a biomarker of severity in macrophage activation syndrome that correlates with hyperferritinemia, elevated aminotransferase levels, and disease flare.

    “interleukin-18 is a biomarker of severity that correlates with hyperferritinemia, elevated aminotransferase levels, and disease flare.45”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Shimizu M, Yokoyama T, Yamada K, et al. Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis. Rheumatology (Oxford) 2010; 49: 1645- 1653. 20472718 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Interleukin-18 synergizes with interleukin-12 or interleukin-15 to stimulate secretion of interferon-γ from T cells and NK cells, and thus promotes Th1-type inflammatory responses.

    “Most important, it synergizes with interleukin-12 or interleukin-15 to stimulate secretion of interferon-γ from T cells and NK cells, and thus promotes Th1-type inflammatory responses.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    TNF is a potent, multifunctional, proinflammatory cytokine that belongs to the TNF-TNF receptor superfamily.

    “TNF is a potent, multifunctional, proinflammatory cytokine that belongs to the TNF–TNF receptor superfamily.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Interleukin-18 is a member of the large interleukin-1 family that has recently been associated with cytokine storm disorders.

    “Interleukin-18 is a member of the large interleukin-1 family40 that has recently been associated with cytokine storm disorders.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity 2013; 39: 1003- 1018. 24332029 PMC3933951 source

      Not checked in the free run.

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

    Interpretationreasoning

    Lower interleukin-6 production by NK cells than by T cells and different cross-talk with myeloid cells may explain the absence of cytokine storm in NK-cell CAR therapy.

    “possibly because of lower interleukin-6 production by NK cells than by T cells and different cross-talk with myeloid cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a recent study of NK-cell CAR therapy, there were no reported cases of cytokine storm or even elevated interleukin-6 levels.

    “In a recent study of NK-cell CAR therapy, there were no reported cases of cytokine storm or even elevated interleukin-6 levels,60”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med 2020; 382: 545- 553. 32023374 PMC7101242 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In blinatumomab-induced cytokine storm, activated T cells initiate the storm and macrophage activation propagates it, and it responds to anti-interleukin-6 antibody therapy.

    “Like CAR T cells, activated T cells initiate the cytokine storm, and macrophage activation propagates blinatumomab-induced cytokine storm, which also responds to anti–interleukin-6 antibody therapy.36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Teachey DT, Rheingold SR, Maude SL, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 2013; 121: 5154- 5157. 23678006 PMC4123427 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients lacking functional perforin have prolonged CD8+ T-cell production of interferon-γ and TNF, and HLH-associated cytokine storm develops in such patients when they are infected with EBV or cytomegalovirus.

    “For example, patients lacking functional perforin, which is critical for resolving infections and inflammation, have prolonged CD8+ T-cell production of interferon-γ and TNF, and HLH-associated cytokine storm develops in such patients when they are infected with EBV or cytomegalovirus.64”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Lykens JE, Terrell CE, Zoller EE, Risma K, Jordan MB. Perforin is a critical physiologic regulator of T-cell activation. Blood 2011; 118: 618- 626. 21606480 PMC3142903 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent studies in mice suggest that cytokines and factors mediating the severity of CAR T-cell-induced cytokine storm are produced by macrophages, not CAR T cells, and can be reversed by interleukin-6 and interleukin-1 blockade.

    “recent studies in mice suggest that the cytokines and factors mediating the severity of cytokine storm are produced not by the CAR T cells but by macrophages and can be reversed by interleukin-6 and interleukin-1 blockade.52-54”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [52] Singh N, Hofmann TJ, Gershenson Z, et al. Monocyte lineage-derived IL-6 does not affect chimeric antigen receptor T-cell function. Cytotherapy 2017; 19: 867- 880. 28506444 PMC6676485 source

      Not checked in the free run.

    • cites [53] Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med 2018; 24: 731- 738. 29808005 PMC6410714 source

      Not checked in the free run.

    • cites [54] Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med 2018; 24: 739- 748. 29808007 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Interleukin-6 is the likely cytokine driver of CAR T-cell-induced cytokine storm because interleukin-6 blockade is highly effective at reversing symptoms and organ dysfunction in most patients.

    “Since interleukin-6 blockade is highly effective at reversing symptoms and organ dysfunction in most patients, it is the likely cytokine driver of cytokine storm induced by CAR T-cell therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Patients with HHV-8-associated multicentric Castleman's disease are immunocompromised as a result of HIV infection or genetic susceptibility, making it difficult to control HHV-8 infection, which is common and typically asymptomatic in the general population.

    “Patients with HHV-8–associated multicentric Castleman’s disease are immunocompromised as a result of human immunodeficiency virus infection or a genetic susceptibility, making it difficult to control the HHV-8 infection, which is a common, typically asymptomatic infection in the general population.69”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood 2020; 135: 1353- 1364. 32106302 source

      Not checked in the free run.

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

    Interpretationnone given

    Infections are most likely the most common trigger of cytokine storm, though data on relative frequencies are limited.

    “Though data on relative frequencies are limited, infections are most likely the most common trigger of cytokine storm.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In patients with genetic susceptibility, the pathogen initiates and T-cell activation propagates cytokine storm.

    “Thus, the pathogen initiates and T-cell activation propagates cytokine storm in patients with a genetic susceptibility.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tocilizumab has minimal and short-lived effect in patients with HHV-8-associated multicentric Castleman's disease, most likely because of viral interleukin-6 signaling independent of the neutralized interleukin-6 receptor.

    “A recent study showed that the effect of tocilizumab in patients with HHV-8–associated multicentric Castleman’s disease was minimal and short-lived, most likely because of viral interleukin-6 signaling that was independent of the neutralized interleukin-6 receptor.70”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Ramaswami R, Lurain K, Peer CJ, et al. Tocilizumab in patients with symptomatic Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Blood 2020; 135: 2316- 2319. 32276276 PMC7316216 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Generalized T-cell and B-cell ablation with alemtuzumab and T-cell ablation with antithymocyte globulin have been reported, and ablation most likely works by depleting pathogenic CD8+ T cells among other cell types.

    “Generalized T-cell and B-cell ablation with alemtuzumab and T-cell ablation with antithymocyte globulin have been reported; ablation most likely works by depleting the pathogenic CD8+ T cells, among other cell types.76”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Marsh RA, Allen CE, McClain KL, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer 2013; 60: 101- 109. 22522603 PMC3410971 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with secondary HLH, viral, autoimmune, or neoplastic disorders trigger cytokine storm, and such patients often have heterozygous polymorphisms in the same genes altered in primary HLH.

    “In patients with secondary HLH, viral, autoimmune, or neoplastic disorders trigger cytokine storm, and such patients often have heterozygous polymorphisms in the same genes that are altered in primary HLH.65,74”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] Zhang M, Bracaglia C, Prencipe G, et al. A heterozygous RAB27A mutation associated with delayed cytolytic granule polarization and hemophagocytic lymphohistiocytosis. J Immunol 2016; 196: 2492- 2503. 26880764 PMC4779709 source

      Not checked in the free run.

    • cites [74] Kaufman KM, Linghu B, Szustakowski JD, et al. Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 2014; 66: 3486- 3495. 25047945 PMC4321811 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rituximab is highly effective in patients with HHV-8-associated multicentric Castleman's disease because B-cell depletion removes the primary reservoir for HHV-8.

    “As with EBV-associated HLH,71 rituximab is highly effective in patients with HHV-8–associated multicentric Castleman’s disease, since B-cell depletion removes the primary reservoir for HHV-8.72”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Chellapandian D, Das R, Zelley K, et al. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol 2013; 162: 376- 382. 23692048 PMC3776423 source

      Not checked in the free run.

    • cites [72] Dalla Pria A, Pinato D, Roe J, Naresh K, Nelson M, Bower M. Relapse of HHV8-positive multicentric Castleman disease following rituximab-based therapy in HIV-positive patients. Blood 2017; 129: 2143- 2147. 28143881 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cytokine storm was reported in patients with SARS and was associated with poor outcomes.

    “Cytokine storm was also reported in patients with SARS and was associated with poor outcomes.86”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Huang K-J, Su I-J, Theron M, et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol 2005; 75: 185- 194. 15602737 PMC7166886 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In autoinflammatory diseases, innate cells are most likely the primary cell drivers, and TNF, interleukin-1, interleukin-18, or a combination of these cytokines probably drives pathogenesis.

    “Given the primary genetic defects and the effective treatments that are available, innate cells are most likely the primary cell drivers involved, and TNF, interleukin-1, interleukin-18, or a combination of these cytokines probably drives pathogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    A recent randomized, controlled trial showing that dexamethasone reduces mortality among the most severe cases of Covid-19 and potentially worsens outcomes in milder cases suggests that excessive, late-stage inflammation contributes to mortality.

    “a recent randomized, controlled trial showing that dexamethasone reduces mortality among the most severe cases of Covid-19, characterized by elevated CRP levels and supplemental oxygen requirements, and potentially worsens outcomes in milder cases suggests that excessive, late-stage inflammation contributes to mortality.88”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 — preliminary report. N Engl J Med. DOI: 10.1056/NEJMoa2021436. 32678530 PMC7383595 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Host immune responses and immune-related symptoms are extremely variable between asymptomatic patients and patients with severe Covid-19, which suggests that host immune dysregulation contributes to pathogenesis in some cases.

    “Host immune responses and immune-related symptoms are extremely variable between asymptomatic patients (who have effective control of SARS-CoV-2) and patients with severe Covid-19 (who are unable to control the virus), which suggests that host immune dysregulation contributes to pathogenesis in some cases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Blocking a cytokine with a low or normal circulating level can be effective if it is a key component of the hyperinflammatory circuit or if its level is potentially elevated in tissue.

    “blocking a cytokine with a low or normal circulating level can be effective if it is a key component of the hyperinflammatory circuit or if its level is potentially elevated in tissue.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Combination therapy has more potential risks than single-agent therapy.

    “combination therapy has more potential risks than single-agent therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    An observational study suggested that patients with Covid-19 have a good response to glucocorticoids when the CRP level is high but a poor response when the level is low.

    “An observational study suggesting that patients with Covid-19 have a good response to glucocorticoids when the CRP level is high but a poor response when the level is low is consistent with these findings.101”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Keller MJ, Kitsis EA, Arora S, et al. Effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with COVID-19. J Hosp Med 2020; 15: 489- 493. 32804611 PMC7518134 source

      Not checked in the free run.

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

    Interpretationnone given

    All targeted agents have target-specific risks.

    “All targeted agents have target-specific risks”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The observation that inhaled interferon-β has a positive effect if given early is consistent with a model in which immunostimulation is helpful early and probably harmful late, whereas immunosuppression is helpful late and harmful early.

    “Likewise, the observation that proinflammatory agents such as inhaled interferon-β have a positive effect if given early in the disease course is consistent with a model in which immunostimulation that enhances antiviral activity is helpful early (and probably harmful late), whereas immunosuppression is helpful late and harmful early.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The immune response to SARS-CoV-2 is critical for controlling viral replication and clearance.

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

    Interpretationnone given

    Pathologic hyperinflammation itself is an immunodeficiency that can put patients at risk for infections.

    “pathologic hyperinflammation itself is an immunodeficiency that can put patients at risk for infections”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Targeted therapeutic approaches to cytokine storm associated with idiopathic multicentric Castleman's disease, HLH, or CAR T-cell therapy have turned deadly conditions into often reversible states.

    “Targeted therapeutic approaches to cytokine storm associated with idiopathic multicentric Castleman’s disease, HLH, or CAR T-cell therapy have turned deadly conditions into often reversible states.”
    Quote in the paperNot a substantial claim
89 of 89

  • The paper relies on this without support.

    The immune system is expected to recognize foreign invaders, respond proportionally to the pathogen burden, and then return to homeostasis.

    “The immune system is expected to recognize foreign invaders, respond proportionally to the pathogen burden, and then return to homeostasis.”

  • The paper relies on this without support.

    Cytokines have short half-lives, which normally prevents them from having effects outside lymphoid tissue and sites of inflammation.

    “Cytokines have short half-lives, which normally prevents them from having effects outside lymphoid tissue and sites of inflammation.”

  • The paper relies on this without support.

    The immune response to SARS-CoV-2 is critical for controlling viral replication and clearance.

    “when the immune response to SARS-CoV-2 is critical in controlling viral replication and clearance.”

  • The paper relies on this without support.

    No unifying definition of cytokine storm exists.

    “No unifying definition of cytokine storm exists”

  • The paper relies on this without support.

    There is much disagreement about what the definition of cytokine storm should be and whether specific conditions such as Covid-19 should be included in the spectrum of cytokine storm disorders.

    “there is much disagreement about what the definition should be and whether specific conditions such as Covid-19 should be included in the spectrum of cytokine storm disorders.”
5 of 5

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

Cited by

Sorted by citations

Related

Authors
Fajgenbaum, D. C., & June, C. H.
Affiliations
  • University of Pennsylvania (US)
  • Parker Institute for Cancer Immunotherapy (US)
Corresponding author
June, Carl H.
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2020-12-03
Volume
383
Issue
23
Pages
2255-2273
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmra2026131
PMC
PMC7727315
OpenAlex
W3112902030
Cited by
3,196
References
113
Citations by year
2026: 304 · 2025: 438 · 2024: 534 · 2023: 592 · 2022: 711 · 2021: 601 · 2020: 10 · 2019: 1 · 2018: 3
FWCI
22.68
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (2r01hl141408-06)
  • National Heart, Lung, and Blood Institute (R01-HL141408)
  • National Cancer Institute (P01CA214278)
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Keywords
cytokine storm, pericarditis, heart disease, CTCAE grading, adverse event definitions
MeSH terms
Cytokine Release Syndrome, COVID-19, Autoimmune Diseases, Bacterial Infections, Blood Proteins, Humans, Interleukins, Virus Diseases, Cytokines, Chemokines

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 2026-10-10.

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

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