Cytokine Storm

In the paper

“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”

What the sources say

• Partly supported

  This source is citation 71, attached to the comparison with EBV-associated HLH; the HHV-8 claim has a separate citation. The Results report clinical improvement in 43% of patients receiving rituximab-containing regimens, but the Discussion says the retrospective study cannot determine rituximab’s efficacy on its own. It therefore does not support calling rituximab highly effective for EBV-associated HLH. (LLM, conf=0.86)

  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 sourceExperimental — accuracy not yet measured
• Not checked yetcites [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

In the paper

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

In the paper

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

In the paper

“These symptoms may be due directly to cytokine-induced tissue damage or acute-phase physiological changes or may result from immune-cell–mediated responses.”

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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”

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“there is disagreement about how these disorders differ from an appropriate inflammatory response”

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“patients may have fatigue, anorexia, headache, rash, diarrhea, arthralgia, myalgia, and neuropsychiatric findings”

In the paper

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

In the paper

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

In the paper

“the fever may be high grade in severe cases”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [24] Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol 2009; 27: 485- 517. 19132915 source

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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”

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“In short, cytokine storm involves an immune response that causes collateral damage, which may be greater than the immediate benefit of the immune response.”

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“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 the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [34] Durand M, Troyanov Y, Laflamme P, Gregoire G. Macrophage activation syndrome treated with anakinra. J Rheumatol 2010; 37: 879- 880. 20360206 source

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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 the paper

“It can signal through two main pathways, referred to as classic cis signaling and trans signaling.”

What the sources say

• Not checked yetcites [38] Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity 2019; 50: 1007- 1023. 30995492 source

In the paper

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

In the paper

“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.”

In the paper

“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 the paper

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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [38] Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity 2019; 50: 1007- 1023. 30995492 source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [42] Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ 2019; 26: 99- 114. 30341423 PMC6294779 source

In the paper

“interleukin-18 is a biomarker of severity that correlates with hyperferritinemia, elevated aminotransferase levels, and disease flare.45”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“TNF is a potent, multifunctional, proinflammatory cytokine that belongs to the TNF–TNF receptor superfamily.”

In the paper

“Interleukin-18 is a member of the large interleukin-1 family40 that has recently been associated with cytokine storm disorders.”

What the sources say

• Not checked yetcites [40] Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity 2013; 39: 1003- 1018. 24332029 PMC3933951 source

In the paper

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

In the paper

“In a recent study of NK-cell CAR therapy, there were no reported cases of cytokine storm or even elevated interleukin-6 levels,60”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [69] Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood 2020; 135: 1353- 1364. 32106302 source

In the paper

“Though data on relative frequencies are limited, infections are most likely the most common trigger of cytokine storm.”

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Cytokine storm was also reported in patients with SARS and was associated with poor outcomes.86”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“combination therapy has more potential risks than single-agent therapy.”

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“All targeted agents have target-specific risks”

In the paper

“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.”

In the paper

“pathologic hyperinflammation itself is an immunodeficiency that can put patients at risk for infections”

In the paper

“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.”