Weathering the Storm: Improving Therapeutic Interventions for Cytokine Storm Syndromes by Targeting Disease Pathogenesis

  • Lehn K. WeaverEmail author
  • Edward M. Behrens
Pediatric Rheumatology (M Becker and J Harris, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Pediatric Rheumatology

Opinion statement

Cytokine storm syndromes require rapid diagnosis and treatment to limit the morbidity and mortality caused by the hyperinflammatory state that characterizes these devastating conditions. Herein, we discuss the current knowledge that guides our therapeutic decision-making and personalization of treatment for patients with cytokine storm syndromes. Firstly, ICU-level supportive care is often required to stabilize patients with fulminant disease while additional diagnostic evaluations proceed to determine the underlying cause of cytokine storm. Pharmacologic interventions should be focused on removing the inciting trigger of inflammation and initiation of an individualized immunosuppressive regimen when immune activation is central to the underlying disease pathophysiology. Monitoring for a clinical response is required to ensure that changes in the therapeutic regimen can be made as clinically warranted. Escalation of immunosuppression may be required if patients respond poorly to the initial therapeutic interventions, while a slow wean of immunosuppression in patients who improve can limit medication-related toxicities. In certain scenarios, a decision must be made whether an individual patient requires hematopoietic cell transplantation to prevent recurrence of disease. Despite these interventions, significant morbidity and mortality remain for cytokine storm patients. Therefore, we use this review to propose a clinical schema to guide current and future attempts to design rational therapeutic interventions for patients suffering from these devastating conditions, which we believe speeds the diagnosis of disease, limits medication-related toxicities, and improves clinical outcomes by targeting the heterogeneous and dynamic mechanisms driving disease in each individual patient.


Hyperinflammation Macrophage activation syndrome Hemophagocytic lymphohistiocytosis Personalized medicine Cytokine storm 


Compliance with Ethical Standards

Conflict of Interest

Lehn K. Weaver declares no conflicts of interest.

Dr. Behrens reports personal fees from AB2Bio, during the conduct of the study. In addition, Dr. Behrens has a patent compositions and methods for treating hemophagocytic lymphohistiocytosis pending to The Children’s Hospital of Philadelphia.

Human and Animal Rights and Informed Consent

With regard to the authors’ research cited in this paper, all procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. In addition, all applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Weaver LK, Behrens EM. Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Curr Opin Rheumatol. 2014;26(5):562–9.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    •• Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10. This article provides an updated definition of sepsis that will facilitate rapid diagnosis of disease and improve consistency for future epidemiologic and clinical trials.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science. 2012;335(6071):936–41.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Schieber AM, Lee YM, Chang MW, Leblanc M, Collins B, Downes M, et al. Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling. Science. 2015;350(6260):558–63.CrossRefPubMedGoogle Scholar
  5. 5.
    Marraffini LA, Sontheimer EJ. CRISPR interference: RNA-directed adaptive immunity in bacteria and archaea. Nat Rev Genet. 2010;11(3):181–90.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    •• Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637. This study provides guidelines for the medical management of patients with sepsis based on supportive care that is known to improve outcomes.CrossRefPubMedGoogle Scholar
  7. 7.
    Levy MM, Rhodes A, Phillips GS, Townsend SR, Schorr CA, Beale R, et al. Surviving sepsis campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med. 2015;43(1):3–12.CrossRefPubMedGoogle Scholar
  8. 8.
    •• Wang A, Huen SC, Luan HH, Yu S, Zhang C, Gallezot JD, et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell. 2016;166(6):1512–25.e12. This preclinical study emphasizes how host metabolism can divergently affect disease outcome depending on whether the infectious trigger was viral or bacterial.CrossRefPubMedGoogle Scholar
  9. 9.
    Hawiger J, Veach RA, Zienkiewicz J. New paradigms in sepsis: from prevention to protection of failing microcirculation. J Thromb Haemost. 2015;13(10):1743–56.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    London NR, Zhu W, Bozza FA, Smith MC, Greif DM, Sorensen LK, et al. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci Transl Med. 2010;2(23):23ra19.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004;104(3):735–43.CrossRefPubMedGoogle Scholar
  12. 12.
    Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041–52.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16.CrossRefPubMedGoogle Scholar
  14. 14.
    Lehmberg K, Nichols KE, Henter JI, Girschikofsky M, Greenwood T, Jordan M, et al. Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica. 2015;100(8):997–1004.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Balamuth NJ, Nichols KE, Paessler M, Teachey DT. Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2007;29(8):569–73.CrossRefPubMedGoogle Scholar
  16. 16.
    Filipovich AH, Chandrakasan S. Pathogenesis of Hemophagocytic Lymphohistiocytosis. Hematol Oncol Clin North Am. 2015;29(5):895–902.CrossRefPubMedGoogle Scholar
  17. 17.
    Henter JI, Samuelsson-Horne A, Arico M, Egeler RM, Elinder G, Filipovich AH, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100(7):2367–73.CrossRefPubMedGoogle Scholar
  18. 18.
    Mahlaoui N, Ouachee-Chardin M, de Saint BG, Neven B, Picard C, Blanche S, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics. 2007;120(3):e622–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Marsh RA, Allen CE, McClain KL, Weinstein JL, Kanter J, Skiles J, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60(1):101–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Seo JJ. Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: recent advances and controversies. Blood Res. 2015;50(3):131–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematol Am Soc Hematol Educ Program. 2013;2013:605–11.Google Scholar
  22. 22.
    Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118(22):5794–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wang Y, Wang Z, Zhang J, Wei Q, Tang R, Qi J, et al. Genetic features of late onset primary hemophagocytic lymphohistiocytosis in adolescence or adulthood. PLoS One. 2014;9(9):e107386.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Meeths M, Bryceson YT, Rudd E, Zheng C, Wood SM, Ramme K, et al. Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations. Pediatr Blood Cancer. 2010;54(4):563–72.PubMedGoogle Scholar
  25. 25.
    Pagel J, Beutel K, Lehmberg K, Koch F, Maul-Pavicic A, Rohlfs AK, et al. Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood. 2012;119(25):6016–24.CrossRefPubMedGoogle Scholar
  26. 26.
    Marsh RA, Satake N, Biroschak J, Jacobs T, Johnson J, Jordan MB, et al. STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr Blood Cancer. 2010;55(1):134–40.PubMedGoogle Scholar
  27. 27.
    Jessen B, Maul-Pavicic A, Ufheil H, Vraetz T, Enders A, Lehmberg K, et al. Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome. Blood. 2011;118(17):4620–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Jessen B, Kogl T, Sepulveda FE, de Saint BG, Aichele P, Ehl S. Graded defects in cytotoxicity determine severity of hemophagocytic lymphohistiocytosis in humans and mice. Front Immunol. 2013;4:448.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jessen B, Bode SF, Ammann S, Chakravorty S, Davies G, Diestelhorst J, et al. The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2. Blood. 2013;121(15):2943–51.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sepulveda FE, Debeurme F, Menasche G, Kurowska M, Cote M, Pachlopnik Schmid J, et al. Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11. Blood. 2013;121(4):595–603.CrossRefPubMedGoogle Scholar
  31. 31.
    Meeths M, Entesarian M, Al-Herz W, Chiang SC, Wood SM, Al-Ateeqi W, et al. Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. Blood. 2010;116(15):2635–43.CrossRefPubMedGoogle Scholar
  32. 32.
    Hackmann Y, Graham SC, Ehl S, Honing S, Lehmberg K, Arico M, et al. Syntaxin binding mechanism and disease-causing mutations in Munc18-2. Proc Natl Acad Sci U S A. 2013;110(47):E4482–91.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ohga S, Matsuzaki A, Nishizaki M, Nagashima T, Kai T, Suda M, et al. Inflammatory cytokines in virus-associated hemophagocytic syndrome. Interferon-gamma as a sensitive indicator of disease activity. Am J Pediatr Hematol Oncol. 1993;15(3):291–8.PubMedGoogle Scholar
  34. 34.
    Henter JI, Elinder G, Soder O, Hansson M, Andersson B, Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991;78(11):2918–22.PubMedGoogle Scholar
  35. 35.
    Pachlopnik Schmid J, Ho CH, Chretien F, Lefebvre JM, Pivert G, Kosco-Vilbois M, et al. Neutralization of IFNgamma defeats haemophagocytosis in LCMV-infected perforin- and Rab27a-deficient mice. EMBO Mol Med. 2009;1(2):112–24.CrossRefPubMedGoogle Scholar
  36. 36.
    Das R, Guan P, Sprague L, Verbist K, Tedrick P, An QA, et al. Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood. 2016;127(13):1666–75.CrossRefPubMedGoogle Scholar
  37. 37.
    Maschalidi S, Sepulveda FE, Garrigue A, Fischer A, de Saint Basile G. Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. Blood. 2016;128(1):60–71.CrossRefPubMedGoogle Scholar
  38. 38.
    Rood JE, Rao S, Paessler M, Kreiger PA, Chu N, Stelekati E, et al. ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice. Blood. 2016;127(4):426–35.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Avau A, Mitera T, Put S, Put K, Brisse E, Filtjens J, et al. Systemic juvenile idiopathic arthritis-like syndrome in mice following stimulation of the immune system with Freund’s complete adjuvant: regulation by interferon-gamma. Arthritis Rheumatol. 2014;66(5):1340–51.CrossRefPubMedGoogle Scholar
  40. 40.
    Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA, Paessler M, et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest. 2011;121(6):2264–77.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Strippoli R, Carvello F, Scianaro R, De Pasquale L, Vivarelli M, Petrini S, et al. Amplification of the response to Toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation syndrome. Arthritis Rheum. 2012;64(5):1680–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Fall N, Barnes M, Thornton S, Luyrink L, Olson J, Ilowite NT, et al. Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum. 2007;56(11):3793–804.CrossRefPubMedGoogle Scholar
  43. 43.
    Yanagimachi M, Naruto T, Miyamae T, Hara T, Kikuchi M, Hara R, et al. Association of IRF5 polymorphisms with susceptibility to macrophage activation syndrome in patients with juvenile idiopathic arthritis. J Rheumatol. 2011;38(4):769–74.CrossRefPubMedGoogle Scholar
  44. 44.
    • Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46(10):1140–6. This study provides evidence for a monogenic disease predisposing to the development of MAS.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    • Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet. 2014;46(10):1135–9. This study provides evidence for a monogenic disease predisposing to the development of MAS.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Canna SW, Goldbach-Mansky R. New monogenic autoinflammatory diseases—a clinical overview. Semin Immunopathol. 2015;37(4):387–94.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine-directed therapies. Annu Rev Med. 2015;66:145–59.CrossRefPubMedGoogle Scholar
  48. 48.
    • Shimizu M, Nakagishi Y, Yachie A. Distinct subsets of patients with systemic juvenile idiopathic arthritis based on their cytokine profiles. Cytokine. 2013;61(2):345–8. This article describes a subset of SJIA patients with an IL-18 predominant serum cytokine signature that predisposes patients to MAS.CrossRefPubMedGoogle Scholar
  49. 49.
    •• Bracaglia C, de Graaf K, Pires Marafon D, Guilhot F, Ferlin W, Prencipe G, et al. Elevated circulating levels of interferon-gamma and interferon-gamma-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2016. This article demonstrates a strong IFNγ signature in the peripheral blood of SJIA patients with MAS that tracks with disease onset and severity.Google Scholar
  50. 50.
    Shimizu M, Yokoyama T, Yamada K, Kaneda H, Wada H, Wada T, 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(9):1645–53.CrossRefGoogle Scholar
  51. 51.
    Shimizu M, Nakagishi Y, Kasai K, Yamasaki Y, Miyoshi M, Takei S, et al. Tocilizumab masks the clinical symptoms of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: the diagnostic significance of interleukin-18 and interleukin-6. Cytokine. 2012;58(2):287–94.CrossRefPubMedGoogle Scholar
  52. 52.
    •• Put K, Vandenhaute J, Avau A, Van Nieuwenhuijze A, Brisse E, Dierckx T, et al. Inflammatory gene expression profile and defective IFN-gamma and granzyme K in natural killer cells of systemic juvenile idiopathic arthritis patients. Arthritis Rheumatol. 2016. This article suggests that defective IL-18-induced NK cell production of IFNγ may protect SJIA patients from developing MAS.Google Scholar
  53. 53.
    Maruyama J, Inokuma S. Cytokine profiles of macrophage activation syndrome associated with rheumatic diseases. J Rheumatol. 2010;37(5):967–73.CrossRefPubMedGoogle Scholar
  54. 54.
    Behrens EM. Caught in the act: Dissecting natural killer cell function in systemic JIA. Arthritis Rheumatol. 2016.Google Scholar
  55. 55.
    Bracaglia C PG, Gatto A, Pardeo M, Lapeyre G, Raganelli L, Marasco E, Insalaco A, Ferlin W, Nelson R, de Min C, and De Benedetti F, editor Anti Interferon-Gamma (IFNg) Monoclonal Antibody Treatment in a Child with NLRC4-Related Disease and Severe Hemophagocytic Lymphohistiocytosis (HLH) [abstract]. 2015 ACR/ARHP Annual Meeting; 2015; San Francisco.Google Scholar
  56. 56.
    Canna SW, Girard C, Malle L, de Jesus A, Romberg N, Kelsen J, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with Interleukin-18 inhibition. J Allergy Clin Immunol. 2016.Google Scholar
  57. 57.
    • Grom AA, Ilowite NT, Pascual V, Brunner HI, Martini A, Lovell D, et al. Rate and clinical presentation of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with canakinumab. Arthritis Rheumatol. 2016;68(1):218–28. This study demonstrates that canakinumab treatment does not alter the rate that MAS occurs in patients with SJIA.CrossRefPubMedGoogle Scholar
  58. 58.
    De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385–95.CrossRefPubMedGoogle Scholar
  59. 59.
    Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat N, Horneff G, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2396–406.CrossRefPubMedGoogle Scholar
  60. 60.
    Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012;13(4):289–98.CrossRefPubMedGoogle Scholar
  61. 61.
    Minoia F, Davi S, Horne A, Bovis F, Demirkaya E, Akikusa J, et al. Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Rheumatol. 2015;42(6):994–1001.CrossRefPubMedGoogle Scholar
  62. 62.
    Quesnel B, Catteau B, Aznar V, Bauters F, Fenaux P. Successful treatment of juvenile rheumatoid arthritis associated haemophagocytic syndrome by cyclosporin A with transient exacerbation by conventional-dose G-CSF. Br J Haematol. 1997;97(2):508–10.PubMedGoogle Scholar
  63. 63.
    Mouy R, Stephan JL, Pillet P, Haddad E, Hubert P, Prieur AM. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J Pediatr. 1996;129(5):750–4.CrossRefPubMedGoogle Scholar
  64. 64.
    Ravelli A, De Benedetti F, Viola S, Martini A. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J Pediatr. 1996;128(2):275–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Emmenegger U, Frey U, Reimers A, Fux C, Semela D, Cottagnoud P, et al. Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes. Am J Hematol. 2001;68(1):4–10.CrossRefPubMedGoogle Scholar
  66. 66.
    Seidel MG, Kastner U, Minkov M, Gadner H. IVIG treatment of adenovirus infection-associated macrophage activation syndrome in a two-year-old boy: case report and review of the literature. Pediatr Hematol Oncol. 2003;20(6):445–51.CrossRefPubMedGoogle Scholar
  67. 67.
    Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20(2):119–22.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Ruella M, Kenderian SS, Shestova O, Klichinsky M, Melenhorst JJ, Wasik MA, et al. Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells (CART) for B cell neoplasms. Leukemia. 2016.Google Scholar
  69. 69.
    Giamarellos-Bourboulis EJ. Failure of treatments based on the cytokine storm theory of sepsis: time for a novel approach. Immunotherapy. 2013;5(3):207–9.CrossRefPubMedGoogle Scholar
  70. 70.
    Salluh JI, Povoa P. Corticosteroids in Severe Sepsis and Septic Shock: A Concise Review. Shock. 2016.Google Scholar
  71. 71.
    Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009;301(23):2445–52.CrossRefPubMedGoogle Scholar
  72. 72.
    Annane D. The role of ACTH and corticosteroids for sepsis and septic shock: an update. Front Endocrinol (Lausanne). 2016;7:70.Google Scholar
  73. 73.
    Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44(2):275–81.CrossRefPubMedGoogle Scholar
  74. 74.
    Rajasekaran S, Kruse K, Kovey K, Davis AT, Hassan NE, Ndika AN, et al. Therapeutic role of anakinra, an interleukin-1 receptor antagonist, in the management of secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction/macrophage activating syndrome in critically ill children*. Pediatr Crit Care Med. 2014;15(5):401–8.CrossRefPubMedGoogle Scholar
  75. 75.
    Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840–51.CrossRefPubMedGoogle Scholar
  76. 76.
    Kempker JA, Martin GS. The changing epidemiology and definitions of sepsis. Clin Chest Med. 2016;37(2):165–79.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Division of Pediatric RheumatologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA

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