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Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Childhood Inflammatory Disorders: Diagnosis and Management

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Abstract

Macrophage activation syndrome (MAS), a form of secondary hemophagocytic lymphohistiocytosis, is a frequently fatal complication of a variety of pediatric inflammatory disorders. MAS has been most commonly associated with systemic juvenile idiopathic arthritis (sJIA), as approximately 10% of children with sJIA develop fulminant MAS, with another 30–40% exhibiting a more subclinical form of the disease. Children with other rheumatologic conditions such as systemic lupus erythematosus and Kawasaki disease are also at risk for MAS. Moreover, MAS also complicates various genetic autoinflammatory disorders such as gain of function mutations in the cytosolic inflammasome NLRC4, pediatric hematologic malignancies (e.g., T-cell lymphoma), and primary immunodeficiencies characterized by immune dysregulation. Disease-specific and broadly inclusive diagnostic criteria have been developed to facilitate the diagnosis of MAS. Recently, simple screening tools such as the serum ferritin to erythrocyte sedimentation rate ratio have been proposed. Early diagnosis and rapid initiation of immunosuppression are essential for the effective management of MAS. With a better understanding of the pathophysiology of MAS and the advent of novel therapeutics, a broad immunosuppressive approach to treatment is giving way to targeted anti-cytokine therapies. These treatments include agents that block interleukin-1 (IL-1), IL-6, IL-18, interferon-γ, as well as inhibitors of downstream targets of cytokine signaling (e.g., Janus kinases). Increased early recognition of MAS among pediatric inflammatory disorders combined with the use of effective and less toxic cytokine-targeted therapies should lower the mortality of this frequently fatal disorder.

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References

  1. Hadchouel M, Prieur AM, Griscelli C. Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: possible relationship to drugs or infection. J Pediatr. 1985;106(4):561–6. https://doi.org/10.1016/s0022-3476(85)80072-x.

    Article  CAS  PubMed  Google Scholar 

  2. Silverman ED, Miller JJ 3rd, Bernstein B, Shafai T. Consumption coagulopathy associated with systemic juvenile rheumatoid arthritis. J Pediatr. 1983;103(6):872–6. https://doi.org/10.1016/s0022-3476(83)80704-5.

    Article  CAS  PubMed  Google Scholar 

  3. Bracaglia C, Prencipe G, De Benedetti F. Macrophage activation syndrome: different mechanisms leading to a one clinical syndrome. Pediatr Rheumatol Online J. 2017;15(1):5. https://doi.org/10.1186/s12969-016-0130-4.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol. 2016;12(5):259–68. https://doi.org/10.1038/nrrheum.2015.179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ravelli A, Davi S, Minoia F, Martini A, Cron RQ. Macrophage activation syndrome. Hematol Oncol Clin N Am. 2015;29(5):927–41. https://doi.org/10.1016/j.hoc.2015.06.010.

    Article  Google Scholar 

  6. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957–9.

    Article  CAS  Google Scholar 

  7. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell. 2003;115(4):461–73.

    Article  CAS  Google Scholar 

  8. zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14(6):827–34. https://doi.org/10.1093/hmg/ddi076.

    Article  CAS  PubMed  Google Scholar 

  9. Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet. 2009;85(4):482–92. https://doi.org/10.1016/j.ajhg.2009.09.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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. https://doi.org/10.1182/blood-2003-10-3413.

    Article  CAS  PubMed  Google Scholar 

  11. Takada H, Takahata Y, Nomura A, Ohga S, Mizuno Y, Hara T. Increased serum levels of interferon-gamma-inducible protein 10 and monokine induced by gamma interferon in patients with haemophagocytic lymphohistiocytosis. Clin Exp Immunol. 2003;133(3):448–53.

    Article  CAS  Google Scholar 

  12. Xu XJ, Tang YM, Song H, Yang SL, Xu WQ, Zhao N, et al. Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children. J Pediatr. 2012;160(6):984–90. https://doi.org/10.1016/j.jpeds.2011.11.046.

    Article  CAS  PubMed  Google Scholar 

  13. Henter JI, Elinder G, Soder O, Hansson M, Andersson B, Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991;78(11):2918–22.

    Article  CAS  Google Scholar 

  14. Jenkins MR, Rudd-Schmidt JA, Lopez JA, Ramsbottom KM, Mannering SI, Andrews DM, et al. Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J Exp Med. 2015;212(3):307–17. https://doi.org/10.1084/jem.20140964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang M, Bracaglia C, Prencipe G, Bemrich-Stolz CJ, Beukelman T, Dimmitt RA, et al. A heterozygous RAB27A mutation associated with delayed cytolytic granule polarization and hemophagocytic lymphohistiocytosis. J Immunol. 2016;196(6):2492–503. https://doi.org/10.4049/jimmunol.1501284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jordan MB, Locatelli F, Allen C, De Benedetti F, Grom AA, Ballabio M, Ferlin G, Nl-0501-04 Study Group, De Min C. A novel targeted approach to the treatment of hemophagocytic lymphohistiocytosis (HLH) with an anti-interferon gamma (IFNγ) monoclonal antibody (mAb), NI-0501: first results from a pilot phase 2 study in children with primary HLH. Blood. 2015;126(23):LBA-3.

    Article  Google Scholar 

  17. Brisse E, Wouters CH, Matthys P. Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders. Cytokine Growth Factor Rev. 2015;26(3):263–80. https://doi.org/10.1016/j.cytogfr.2014.10.001.

    Article  CAS  PubMed  Google Scholar 

  18. Brisse E, Wouters CH, Andrei G, Matthys P. How viruses contribute to the pathogenesis of hemophagocytic lymphohistiocytosis. Front Immunol. 2017;8:1102. https://doi.org/10.3389/fimmu.2017.01102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lehmberg K, Sprekels B, Nichols KE, Woessmann W, Muller I, Suttorp M, et al. Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol. 2015;170(4):539–49. https://doi.org/10.1111/bjh.13462.

    Article  PubMed  Google Scholar 

  20. Machaczka M, Vaktnas J, Klimkowska M, Hagglund H. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center. Leuk Lymphoma. 2011;52(4):613–9. https://doi.org/10.3109/10428194.2010.551153.

    Article  PubMed  Google Scholar 

  21. Grom AA, Villanueva J, Lee S, Goldmuntz EA, Passo MH, Filipovich A. Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. J Pediatr. 2003;142(3):292–6. https://doi.org/10.1067/mpd.2003.110.

    Article  CAS  PubMed  Google Scholar 

  22. Cifaldi L, Prencipe G, Caiello I, Bracaglia C, Locatelli F, De Benedetti F, et al. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol. 2015;67(11):3037–46. https://doi.org/10.1002/art.39295.

    Article  CAS  PubMed  Google Scholar 

  23. Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A, et al. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther. 2005;7(1):R30–7. https://doi.org/10.1186/ar1453.

    Article  CAS  PubMed  Google Scholar 

  24. Hazen MM, Woodward AL, Hofmann I, Degar BA, Grom A, Filipovich AH, et al. Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Arthritis Rheum. 2008;58(2):567–70. https://doi.org/10.1002/art.23199.

    Article  CAS  PubMed  Google Scholar 

  25. Kaufman KM, Linghu B, Szustakowski JD, Husami A, Yang F, Zhang K, et al. Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheumatol. 2014;66(12):3486–95. https://doi.org/10.1002/art.38793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Vastert SJ, van Wijk R, D’Urbano LE, de Vooght KM, de Jager W, Ravelli A, et al. Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatology. 2010;49(3):441–9. https://doi.org/10.1093/rheumatology/kep418.

    Article  CAS  PubMed  Google Scholar 

  27. Schulert GS, Zhang M, Fall N, Husami A, Kissell D, Hanosh A, et al. Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza. J Infect Dis. 2016;213(7):1180–8. https://doi.org/10.1093/infdis/jiv550.

    Article  CAS  PubMed  Google Scholar 

  28. Bracaglia CSE, Da Ros M, De Fusco C, Micalizzi M, Cetica V, Ciambotti B, Coniglio ML, Insalaco A, De Benedetti F, Arico M. Mutations of familial hemophagocytic lymphohistiocytosis (FHL) related genes and abnormalities of cytotoxicity function tests in patients with macrophage activation syndrome (MAS) occuring in systemic juvenile idiopathic arthritis (sJIA). Pediatr Rheumatol Online J. 2014;12(Supp1):53.

    Article  Google Scholar 

  29. 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. 2017;76(1):166–72. https://doi.org/10.1136/annrheumdis-2015-209020.

    Article  CAS  PubMed  Google Scholar 

  30. Put K, Avau A, Brisse E, Mitera T, Put S, Proost P, et al. Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-gamma. Rheumatology. 2015;54(8):1507–17. https://doi.org/10.1093/rheumatology/keu524.

    Article  PubMed  Google Scholar 

  31. Weiss ES, Girard-Guyonvarc’h C, Holzinger D, de Jesus AA, Tariq Z, Picarsic J, et al. Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood. 2018;131(13):1442–55. https://doi.org/10.1182/blood-2017-12-820852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 Investig. 2011;121(6):2264–77. https://doi.org/10.1172/JCI43157.

    Article  CAS  PubMed  Google Scholar 

  33. Prencipe G, Caiello I, Pascarella A, Grom AA, Bracaglia C, Chatel L, et al. Neutralization of IFN-gamma reverts clinical and laboratory features in a mouse model of macrophage activation syndrome. J Allergy Clin Immunol. 2018;141(4):1439–49. https://doi.org/10.1016/j.jaci.2017.07.021.

    Article  CAS  PubMed  Google Scholar 

  34. 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. https://doi.org/10.1002/art.33496.

    Article  CAS  PubMed  Google Scholar 

  35. Strippoli R, Caiello I, De Benedetti F. Reaching the threshold: a multilayer pathogenesis of macrophage activation syndrome. J Rheumatol. 2013;40(6):761–7. https://doi.org/10.3899/jrheum.121233.

    Article  CAS  PubMed  Google Scholar 

  36. Brisse E, Wouters CH, Matthys P. Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities. Br J Haematol. 2016;174(2):203–17. https://doi.org/10.1111/bjh.14147.

    Article  CAS  PubMed  Google Scholar 

  37. Behrens EM, Beukelman T, Paessler M, Cron RQ. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol. 2007;34(5):1133–8.

    PubMed  Google Scholar 

  38. Minoia F, Davi S, Horne A, Demirkaya E, Bovis F, Li C, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol. 2014;66(11):3160–9. https://doi.org/10.1002/art.38802.

    Article  PubMed  Google Scholar 

  39. Bleesing J, Prada A, Siegel DM, Villanueva J, Olson J, Ilowite NT, et al. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum. 2007;56(3):965–71. https://doi.org/10.1002/art.22416.

    Article  CAS  PubMed  Google Scholar 

  40. Gavand PE, Serio I, Arnaud L, Costedoat-Chalumeau N, Carvelli J, Dossier A, et al. Clinical spectrum and therapeutic management of systemic lupus erythematosus-associated macrophage activation syndrome: a study of 103 episodes in 89 adult patients. Autoimmun Rev. 2017;16(7):743–9. https://doi.org/10.1016/j.autrev.2017.05.010.

    Article  CAS  PubMed  Google Scholar 

  41. Borgia RE, Gerstein M, Levy DM, Silverman ED, Hiraki LT. Features, treatment, and outcomes of macrophage activation syndrome in childhood-onset systemic lupus erythematosus. Arthritis Rheumatol. 2018;70(4):616–24. https://doi.org/10.1002/art.40417.

    Article  CAS  PubMed  Google Scholar 

  42. Latino GA, Manlhiot C, Yeung RS, Chahal N, McCrindle BW. Macrophage activation syndrome in the acute phase of Kawasaki disease. J Pediatr Hematol Oncol. 2010;32(7):527–31. https://doi.org/10.1097/MPH.0b013e3181dccbf4.

    Article  PubMed  Google Scholar 

  43. Bennett TD, Fluchel M, Hersh AO, Hayward KN, Hersh AL, Brogan TV, et al. Macrophage activation syndrome in children with systemic lupus erythematosus and children with juvenile idiopathic arthritis. Arthritis Rheum. 2012;64(12):4135–42. https://doi.org/10.1002/art.34661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang W, Gong F, Zhu W, Fu S, Zhang Q. Macrophage activation syndrome in Kawasaki disease: more common than we thought? Semin Arthritis Rheum. 2015;44(4):405–10. https://doi.org/10.1016/j.semarthrit.2014.07.007.

    Article  CAS  PubMed  Google Scholar 

  45. Francois B, Trimoreau F, Vignon P, Fixe P, Praloran V, Gastinne H. Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor. Am J Med. 1997;103(2):114–20. https://doi.org/10.1016/s0002-9343(97)00136-8.

    Article  CAS  PubMed  Google Scholar 

  46. Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013;14(4):307–8. https://doi.org/10.1038/ni.2554.

    Article  CAS  PubMed  Google Scholar 

  47. Strauss R, Neureiter D, Westenburger B, Wehler M, Kirchner T, Hahn EG. Multifactorial risk analysis of bone marrow histiocytic hyperplasia with hemophagocytosis in critically ill medical patients—a postmortem clinicopathologic analysis. Crit Care Med. 2004;32(6):1316–21. https://doi.org/10.1097/01.ccm.0000127779.24232.15.

    Article  PubMed  Google Scholar 

  48. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001;85(5):421–6. https://doi.org/10.1136/adc.85.5.421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology. 2001;40(11):1285–92.

    Article  CAS  Google Scholar 

  50. Hiraki LT, Silverman ED. Genomics of systemic lupus erythematosus: insights gained by studying monogenic young-onset systemic lupus erythematosus. Rheum Dis Clin N Am. 2017;43(3):415–34. https://doi.org/10.1016/j.rdc.2017.04.005.

    Article  Google Scholar 

  51. Bader-Meunier B, Florkin B, Sibilia J, Acquaviva C, Hachulla E, Grateau G, et al. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics. 2011;128(1):e152–9. https://doi.org/10.1542/peds.2010-3639.

    Article  PubMed  Google Scholar 

  52. Rossi-Semerano L, Hermeziu B, Fabre M, Kone-Paut I. Macrophage activation syndrome revealing familial Mediterranean fever. Arthritis Care Res. 2011;63(5):780–3. https://doi.org/10.1002/acr.20418.

    Article  CAS  Google Scholar 

  53. Horneff G, Rhouma A, Weber C, Lohse P. Macrophage activation syndrome as the initial manifestation of tumour necrosis factor receptor 1-associated periodic syndrome (TRAPS). Clin Exp Rheumatol. 2013;31(3 Suppl 77):99–102.

    PubMed  Google Scholar 

  54. Rigante D, Emmi G, Fastiggi M, Silvestri E, Cantarini L. Macrophage activation syndrome in the course of monogenic autoinflammatory disorders. Clin Rheumatol. 2015;34(8):1333–9. https://doi.org/10.1007/s10067-015-2923-0.

    Article  PubMed  Google Scholar 

  55. 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. https://doi.org/10.1038/ng.3089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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. https://doi.org/10.1038/ng.3066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol. 2006;7(6):569–75. https://doi.org/10.1038/ni1344.

    Article  CAS  PubMed  Google Scholar 

  58. Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J Exp Med. 2007;204(13):3235–45. https://doi.org/10.1084/jem.20071239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992;356(6372):768–74. https://doi.org/10.1038/356768a0.

    Article  CAS  PubMed  Google Scholar 

  60. Volker-Touw CM, de Koning HD, Giltay JC, de Kovel CG, van Kempen TS, Oberndorff KM, et al. Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4-related autoinflammatory disease, expansion of the phenotype. Br J Dermatol. 2017;176(1):244–8. https://doi.org/10.1111/bjd.14757.

    Article  CAS  PubMed  Google Scholar 

  61. Canna SW, Girard C, Malle L, de Jesus A, Romberg N, Kelsen J, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol. 2017;139(5):1698–701. https://doi.org/10.1016/j.jaci.2016.10.022.

    Article  CAS  PubMed  Google Scholar 

  62. Canna SW, Behrens EM. Not all hemophagocytes are created equally: appreciating the heterogeneity of the hemophagocytic syndromes. Curr Opin Rheumatol. 2012;24(1):113–8. https://doi.org/10.1097/BOR.0b013e32834dd37e.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Tesi B, Bryceson YT. HLH: genomics illuminates pathophysiological diversity. Blood. 2018;132(1):5–7. https://doi.org/10.1182/blood-2018-05-845818.

    Article  CAS  PubMed  Google Scholar 

  64. Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16. https://doi.org/10.1016/S0140-6736(13)61048-X.

    Article  PubMed  Google Scholar 

  65. Strenger V, Merth G, Lackner H, Aberle SW, Kessler HH, Seidel MG, et al. Malignancy and chemotherapy induced haemophagocytic lymphohistiocytosis in children and adolescents-a single centre experience of 20 years. Ann Hematol. 2018;97(6):989–98. https://doi.org/10.1007/s00277-018-3254-4.

    Article  PubMed  PubMed Central  Google Scholar 

  66. 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. https://doi.org/10.1097/PPO.0000000000000035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Faitelson Y, Grunebaum E. Hemophagocytic lymphohistiocytosis and primary immune deficiency disorders. Clin Immunol. 2014;155(1):118–25. https://doi.org/10.1016/j.clim.2014.09.008.

    Article  CAS  PubMed  Google Scholar 

  68. Pachlopnik Schmid J, Canioni D, Moshous D, Touzot F, Mahlaoui N, Hauck F, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011;117(5):1522–9. https://doi.org/10.1182/blood-2010-07-298372.

    Article  CAS  PubMed  Google Scholar 

  69. Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature. 1998;395(6701):462–9. https://doi.org/10.1038/26683.

    Article  CAS  PubMed  Google Scholar 

  70. Rigaud S, Fondaneche MC, Lambert N, Pasquier B, Mateo V, Soulas P, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006;444(7115):110–4. https://doi.org/10.1038/nature05257.

    Article  CAS  PubMed  Google Scholar 

  71. Wada T, Kanegane H, Ohta K, Katoh F, Imamura T, Nakazawa Y, et al. Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency. Cytokine. 2014;65(1):74–8. https://doi.org/10.1016/j.cyto.2013.09.007.

    Article  CAS  PubMed  Google Scholar 

  72. Huck K, Feyen O, Niehues T, Ruschendorf F, Hubner N, Laws HJ, et al. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J Clin Investig. 2009;119(5):1350–8. https://doi.org/10.1172/jci37901.

    Article  CAS  PubMed  Google Scholar 

  73. Alkhairy OK, Perez-Becker R, Driessen GJ, Abolhassani H, van Montfrans J, Borte S, et al. Novel mutations in TNFRSF7/CD27: clinical, immunologic, and genetic characterization of human CD27 deficiency. J Allergy Clin Immunol. 2015;136(3):703–12. https://doi.org/10.1016/j.jaci.2015.02.022.

    Article  CAS  PubMed  Google Scholar 

  74. Li FY, Chaigne-Delalande B, Su H, Uzel G, Matthews H, Lenardo MJ. XMEN disease: a new primary immunodeficiency affecting Mg2 + regulation of immunity against Epstein–Barr virus. Blood. 2014;123(14):2148–52. https://doi.org/10.1182/blood-2013-11-538686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nagle DL, Karim MA, Woolf EA, Holmgren L, Bork P, Misumi DJ, et al. Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet. 1996;14(3):307–11. https://doi.org/10.1038/ng1196-307.

    Article  CAS  PubMed  Google Scholar 

  76. Menasche G, Pastural E, Feldmann J, Certain S, Ersoy F, Dupuis S, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000;25(2):173–6. https://doi.org/10.1038/76024.

    Article  CAS  PubMed  Google Scholar 

  77. Clark RH, Stinchcombe JC, Day A, Blott E, Booth S, Bossi G, et al. Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat Immunol. 2003;4(11):1111–20. https://doi.org/10.1038/ni1000.

    Article  CAS  PubMed  Google Scholar 

  78. Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol. 2019;10:119. https://doi.org/10.3389/fimmu.2019.00119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Filipovich AH, Chandrakasan S. Pathogenesis of hemophagocytic lymphohistiocytosis. Hematol Oncol Clin N Am. 2015;29(5):895–902. https://doi.org/10.1016/j.hoc.2015.06.007.

    Article  Google Scholar 

  80. Parekh C, Hofstra T, Church JA, Coates TD. Hemophagocytic lymphohistiocytosis in children with chronic granulomatous disease. Pediatr Blood Cancer. 2011;56(3):460–2. https://doi.org/10.1002/pbc.22830.

    Article  PubMed  Google Scholar 

  81. Valentine G, Thomas TA, Nguyen T, Lai YC. Chronic granulomatous disease presenting as hemophagocytic lymphohistiocytosis: a case report. Pediatrics. 2014;134(6):e1727–30. https://doi.org/10.1542/peds.2014-2175.

    Article  PubMed  Google Scholar 

  82. Alvarez-Cardona A, Rodriguez-Lozano AL, Blancas-Galicia L, Rivas-Larrauri FE, Yamazaki-Nakashimada MA. Intravenous immunoglobulin treatment for macrophage activation syndrome complicating chronic granulomatous disease. J Clin Immunol. 2012;32(2):207–11. https://doi.org/10.1007/s10875-011-9616-5.

    Article  PubMed  Google Scholar 

  83. Canna SW, Behrens EM. Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr Clin N Am. 2012;59(2):329–44. https://doi.org/10.1016/j.pcl.2012.03.002.

    Article  Google Scholar 

  84. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31. https://doi.org/10.1002/pbc.21039.

    Article  PubMed  Google Scholar 

  85. Ho C, Yao X, Tian L, Li FY, Podoltsev N, Xu ML. Marrow assessment for hemophagocytic lymphohistiocytosis demonstrates poor correlation with disease probability. Am J Clin Pathol. 2014;141(1):62–71. https://doi.org/10.1309/AJCPMD5TJEFOOVBW.

    Article  PubMed  Google Scholar 

  86. Arico M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996;10(2):197–203.

    CAS  PubMed  Google Scholar 

  87. Minoia F, Bovis F, Davi S, Insalaco A, Lehmberg K, Shenoi S, et al. Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation syndrome. J Pediatr. 2017;189(72–8):e3. https://doi.org/10.1016/j.jpeds.2017.06.005.

    Article  Google Scholar 

  88. Gars E, Purington N, Scott G, Chisholm K, Gratzinger D, Martin BA, et al. Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis. Haematologica. 2018;103(10):1635–41. https://doi.org/10.3324/haematol.2017.186627.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(6):1227–35. https://doi.org/10.1002/pbc.21423.

    Article  PubMed  Google Scholar 

  90. Schram AM, Campigotto F, Mullally A, Fogerty A, Massarotti E, Neuberg D, et al. Marked hyperferritinemia does not predict for HLH in the adult population. Blood. 2015;125(10):1548–52. https://doi.org/10.1182/blood-2014-10-602607.

    Article  CAS  PubMed  Google Scholar 

  91. Lehmberg K, McClain KL, Janka GE, Allen CE. Determination of an appropriate cut-off value for ferritin in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2014;61(11):2101–3. https://doi.org/10.1002/pbc.25058.

    Article  CAS  PubMed  Google Scholar 

  92. Saeed H, Woods RR, Lester J, Herzig R, Gul Z, Monohan G. Evaluating the optimal serum ferritin level to identify hemophagocytic lymphohistiocytosis in the critical care setting. Int J Hematol. 2015;102(2):195–9. https://doi.org/10.1007/s12185-015-1813-1.

    Article  CAS  PubMed  Google Scholar 

  93. Takada H, Ohga S, Mizuno Y, Suminoe A, Matsuzaki A, Ihara K, et al. Oversecretion of IL-18 in haemophagocytic lymphohistiocytosis: a novel marker of disease activity. Br J Haematol. 1999;106(1):182–9.

    Article  CAS  Google Scholar 

  94. 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. 2010;49(9):1645–53. https://doi.org/10.1093/rheumatology/keq133.

    Article  CAS  PubMed  Google Scholar 

  95. Davi S, Minoia F, Pistorio A, Horne A, Consolaro A, Rosina S, et al. Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2014;66(10):2871–80. https://doi.org/10.1002/art.38769.

    Article  CAS  PubMed  Google Scholar 

  96. Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, et al. 2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol. 2016;68(3):566–76. https://doi.org/10.1002/art.39332.

    Article  PubMed  Google Scholar 

  97. Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, et al. 2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2016;75(3):481–9. https://doi.org/10.1136/annrheumdis-2015-208982.

    Article  CAS  PubMed  Google Scholar 

  98. Shimizu M, Mizuta M, Yasumi T, Iwata N, Okura Y, Kinjo N, et al. Validation of classification criteria of macrophage activation syndrome in Japanese patients with systemic juvenile idiopathic arthritis. Arthritis Care Res. 2018;70(9):1412–5. https://doi.org/10.1002/acr.23482.

    Article  CAS  Google Scholar 

  99. Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, et al. Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. RMD Open. 2016;2(1):e000161. https://doi.org/10.1136/rmdopen-2015-000161.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Halyabar O, Chang MH, Schoettler ML, Schwartz MA, Baris EH, Benson LA, et al. Calm in the midst of cytokine storm: a collaborative approach to the diagnosis and treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Pediatr Rheumatol Online J. 2019;17(1):7. https://doi.org/10.1186/s12969-019-0309-6.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Schulert GS, Minoia F, Bohnsack J, Cron RQ, Hashad S, Kon EPI, et al. Effect of biologic therapy on clinical and laboratory features of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis. Arthritis Care Res. 2018;70(3):409–19. https://doi.org/10.1002/acr.23277.

    Article  CAS  Google Scholar 

  102. Ahn SS, Yoo BW, Jung SM, Lee SW, Park YB, Song JJ. Application of the 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome in patients with adult-onset still disease. J Rheumatol. 2017;44(7):996–1003. https://doi.org/10.3899/jrheum.161286.

    Article  CAS  PubMed  Google Scholar 

  103. Ahn SS, Yoo BW, Jung SM, Lee SW, Park YB, Song JJ. In-hospital mortality in febrile lupus patients based on 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome. Semin Arthritis Rheum. 2017;47(2):216–21. https://doi.org/10.1016/j.semarthrit.2017.02.002.

    Article  PubMed  Google Scholar 

  104. Tada Y, Inokuchi S, Maruyama A, Suematsu R, Sakai M, Sadanaga Y, et al. Are the 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome applicable to patients with adult-onset Still’s disease? Rheumatol Int. 2019;39(1):97–104. https://doi.org/10.1007/s00296-018-4114-1.

    Article  CAS  PubMed  Google Scholar 

  105. Parodi A, Davi S, Pringe AB, Pistorio A, Ruperto N, Magni-Manzoni S, et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients. Arthritis Rheum. 2009;60(11):3388–99. https://doi.org/10.1002/art.24883.

    Article  CAS  PubMed  Google Scholar 

  106. Minoia F, Bovis F, Davi S, Horne A, Fischbach M, Frosch M, et al. Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2019. https://doi.org/10.1136/annrheumdis-2019-215211.

    Article  PubMed  Google Scholar 

  107. Gorelik M, Fall N, Altaye M, Barnes MG, Thompson SD, Grom AA, et al. Follistatin-like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential biomarkers for dysregulated gene expression and macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2013;40(7):1191–9. https://doi.org/10.3899/jrheum.121131.

    Article  CAS  PubMed  Google Scholar 

  108. Eloseily EMA, Minoia F, Crayne CB, Beukelman T, Ravelli A, Cron RQ. Ferritin to erythrocytoe sedimentation rate ratio: simple measure to identify macrophage activation syndrome in systemic juvenile idiopathic arthritis. ACR Open Rheumatol. 2019. https://doi.org/10.1002/acr2.11048.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613–20. https://doi.org/10.1002/art.38690.

    Article  PubMed  Google Scholar 

  110. Debaugnies F, Mahadeb B, Ferster A, Meuleman N, Rozen L, Demulder A, et al. Performances of the H-Score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients. Am J Clin Pathol. 2016;145(6):862–70. https://doi.org/10.1093/ajcp/aqw076.

    Article  CAS  PubMed  Google Scholar 

  111. 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. https://doi.org/10.1182/blood-2011-07-370148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041–52. https://doi.org/10.1182/blood-2011-03-278127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140(3):221–30.

    Article  CAS  Google Scholar 

  114. Bergsten E, Horne A, Arico M, Astigarraga I, Egeler RM, Filipovich AH, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728–38. https://doi.org/10.1182/blood-2017-06-788349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, et al. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol. 2013;162(3):376–82. https://doi.org/10.1111/bjh.12386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 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. https://doi.org/10.1182/blood-2002-01-0172.

    Article  CAS  PubMed  Google Scholar 

  117. Ehl S, Astigarraga I, von Bahr Greenwood T, Hines M, Horne A, Ishii E, et al. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH steering committee of the histiocyte society. J Allergy Clin Immunol Pract. 2018;6(5):1508–17. https://doi.org/10.1016/j.jaip.2018.05.031.

    Article  PubMed  Google Scholar 

  118. 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.

    Article  CAS  Google Scholar 

  119. Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology. 2011;50(2):417–9. https://doi.org/10.1093/rheumatology/keq218.

    Article  CAS  PubMed  Google Scholar 

  120. Chen RL, Lin KH, Lin DT, Su IJ, Huang LM, Lee PI, et al. Immunomodulation treatment for childhood virus-associated haemophagocytic lymphohistiocytosis. Br J Haematol. 1995;89(2):282–90. https://doi.org/10.1111/j.1365-2141.1995.tb03302.x.

    Article  CAS  PubMed  Google Scholar 

  121. 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.

    Article  CAS  Google Scholar 

  122. Fisher CJ Jr., Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271(23):1836–43.

    Article  Google Scholar 

  123. DeWitt EM, Kimura Y, Beukelman T, Nigrovic PA, Onel K, Prahalad S, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res. 2012;64(7):1001–10. https://doi.org/10.1002/acr.21625.

    Article  CAS  Google Scholar 

  124. Quartier P, Allantaz F, Cimaz R, Pillet P, Messiaen C, Bardin C, et al. A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis. 2011;70(5):747–54. https://doi.org/10.1136/ard.2010.134254.

    Article  CAS  PubMed  Google Scholar 

  125. Nigrovic PA, Mannion M, Prince FH, Zeft A, Rabinovich CE, van Rossum MA, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 2011;63(2):545–55. https://doi.org/10.1002/art.30128.

    Article  CAS  PubMed  Google Scholar 

  126. Ter Haar NM, van Dijkhuizen EHP, Swart JF, van Royen-Kerkhof A, El Idrissi A, Leek AP, et al. Treatment to target using recombinant interleukin-1 receptor antagonist as first-line monotherapy in new-onset systemic juvenile idiopathic arthritis: results from a five-year follow-up study. Arthritis Rheumatol. 2019;71(7):1163–73. https://doi.org/10.1002/art.40865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Durand M, Troyanov Y, Laflamme P, Gregoire G. Macrophage activation syndrome treated with anakinra. J Rheumatol. 2010;37(4):879–80. https://doi.org/10.3899/jrheum.091046.

    Article  PubMed  Google Scholar 

  128. Bruck N, Suttorp M, Kabus M, Heubner G, Gahr M, Pessler F. Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis. 2011;17(1):23–7. https://doi.org/10.1097/RHU.0b013e318205092d.

    Article  Google Scholar 

  129. Kelly A, Ramanan AV. A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol. 2008;4(11):615–20. https://doi.org/10.1038/ncprheum0919.

    Article  CAS  PubMed  Google Scholar 

  130. Kahn PJ, Cron RQ. Higher-dose Anakinra is effective in a case of medically refractory macrophage activation syndrome. J Rheumatol. 2013;40(5):743–4. https://doi.org/10.3899/jrheum.121098.

    Article  CAS  PubMed  Google Scholar 

  131. Lenert A, Yao Q. Macrophage activation syndrome complicating adult onset Still’s disease: a single center case series and comparison with literature. Semin Arthritis Rheum. 2016;45(6):711–6. https://doi.org/10.1016/j.semarthrit.2015.11.002.

    Article  PubMed  Google Scholar 

  132. Neel A, Wahbi A, Tessoulin B, Boileau J, Carpentier D, Decaux O, et al. Diagnostic and management of life-threatening Adult-Onset Still Disease: a French nationwide multicenter study and systematic literature review. Crit Care. 2018;22(1):88. https://doi.org/10.1186/s13054-018-2012-2.

    Article  PubMed  PubMed Central  Google Scholar 

  133. 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 J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc. 2014;15(5):401–8. https://doi.org/10.1097/PCC.0000000000000078.

    Article  Google Scholar 

  134. 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. https://doi.org/10.1097/CCM.0000000000001402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wohlfarth P, Agis H, Gualdoni GA, Weber J, Staudinger T, Schellongowski P, et al. Interleukin 1 receptor antagonist anakinra, intravenous immunoglobulin, and corticosteroids in the management of critically ill adult patients with hemophagocytic lymphohistiocytosis. J Intensive Care Med. 2017. https://doi.org/10.1177/0885066617711386.

    Article  PubMed  Google Scholar 

  136. Kumar B, Aleem S, Saleh H, Petts J, Ballas ZK. A personalized diagnostic and treatment approach for macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis in adults. J Clin Immunol. 2017;37(7):638–43. https://doi.org/10.1007/s10875-017-0439-x.

    Article  PubMed  Google Scholar 

  137. Gabay C, Fautrel B, Rech J, Spertini F, Feist E, Kotter I, et al. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still’s disease. Ann Rheum Dis. 2018;77(6):840–7. https://doi.org/10.1136/annrheumdis-2017-212608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. De Benedetti F, Borgan P, Grom A, Quartier P, Schneider R, De Graaf K, et al. OP0204 Emapalumab, an interferon gamma-blocking monoclonal antibody, in patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis [abstract]. Ann Rheum Dis. 2019;78:178.

    Google Scholar 

  139. Lounder DT, Bin Q, de Min C, Jordan MB. Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections. Blood Adv. 2019;3(1):47–50. https://doi.org/10.1182/bloodadvances.2018025858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Bracaglia C, Prencipe G, Insalaco A, Caiello I, Marucci G, Pecoraro R, et al. Emapalumab, an anti-interferon gamma monoclonal antibody in two patients with NLRC4-related disease and severe hemophagocytic lymphohistiocytosis (HLH) [abstract]. Arthritis Rheumatol. 2018;70(suppl 9):1547.

    Google Scholar 

  141. Lam MT, Coppola S, Krumbach OH, Prencipe G, Insalaco A, Cifaldi C, et al. FRI0540 A novel autoinflammatory disease characterized by neonatal-onset cytopenia with autoinflammation, rash, and hemophagocytosis (NOCARH) due to aberrant CDC42 function [abstract]. Ann Rheum Dis. 2019;78(suppl 2):964.

    Google Scholar 

  142. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17. https://doi.org/10.1056/NEJMoa1407222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121(26):5154–7. https://doi.org/10.1182/blood-2013-02-485623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Villarino AV, Kanno Y, O’Shea JJ. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol. 2017;18(4):374–84. https://doi.org/10.1038/ni.3691.

    Article  CAS  PubMed  Google Scholar 

  145. 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. https://doi.org/10.1182/blood-2015-12-684399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Zandvakili I, Conboy CB, Ayed AO, Cathcart-Rake EJ, Tefferi A. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: a second experience. Am J Hematol. 2018;93(5):E123–5. https://doi.org/10.1002/ajh.25063.

    Article  PubMed  Google Scholar 

  147. Slostad J, Hoversten P, Haddox CL, Cisak K, Paludo J, Tefferi A. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: a single patient experience. Am J Hematol. 2018;93(2):E47–9. https://doi.org/10.1002/ajh.24971.

    Article  PubMed  Google Scholar 

  148. Broglie L, Pommert L, Rao S, Thakar M, Phelan R, Margolis D, et al. Ruxolitinib for treatment of refractory hemophagocytic lymphohistiocytosis. Blood Adv. 2017;1(19):1533–6. https://doi.org/10.1182/bloodadvances.2017007526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Mahlaoui N, Ouachee-Chardin M, de Saint Basile G, 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. https://doi.org/10.1542/peds.2006-3164.

    Article  PubMed  Google Scholar 

  150. Marsh RA, Jordan MB, Talano JA, Nichols KE, Kumar A, Naqvi A, et al. Salvage therapy for refractory hemophagocytic lymphohistiocytosis: a review of the published experience. Pediatr Blood Cancer. 2017. https://doi.org/10.1002/pbc.26308.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Coca A, Bundy KW, Marston B, Huggins J, Looney RJ. Macrophage activation syndrome: serological markers and treatment with anti-thymocyte globulin. Clin Immunol. 2009;132(1):10–8. https://doi.org/10.1016/j.clim.2009.02.005.

    Article  CAS  PubMed  Google Scholar 

  152. 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. https://doi.org/10.1002/pbc.24188.

    Article  CAS  PubMed  Google Scholar 

  153. Nusshag C, Morath C, Zeier M, Weigand MA, Merle U, Brenner T. Hemophagocytic lymphohistiocytosis in an adult kidney transplant recipient successfully treated by plasmapheresis: a case report and review of the literature. Medicine. 2017;96(50):e9283. https://doi.org/10.1097/MD.0000000000009283.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Kinjo N, Hamada K, Hirayama C, Shimizu M. Role of plasma exchange, leukocytapheresis, and plasma diafiltration in management of refractory macrophage activation syndrome. J Clin Apheresis. 2018;33(1):117–20. https://doi.org/10.1002/jca.21570.

    Article  PubMed  Google Scholar 

  155. Simon DW, Aneja R, Carcillo JA, Halstead ES. Plasma exchange, methylprednisolone, IV immune globulin, and now anakinra support continued PICU equipoise in management of hyperferritinemia-associated sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome/secondary hemophagocytic lymphohistiocytosis syndrome*. Pediatr Crit Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc. 2014;15(5):486–8. https://doi.org/10.1097/PCC.0000000000000098.

    Article  Google Scholar 

  156. Demirkol D, Yildizdas D, Bayrakci B, Karapinar B, Kendirli T, Koroglu TF, et al. Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment? Crit Care. 2012;16(2):R52. https://doi.org/10.1186/cc11256.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Immunology, Boston Children’s Hospital, 1 Blackfan Circle, 10th Floor Karp Family Research Building, Boston, MA, 02115, USA

    Lauren A. Henderson

  2. Division of Pediatric Rheumatology, Children’s of Alabama, 1600 7th Ave. S., CPPN, suite G10, Birmingham, AL, 35233-1711, USA

    Randy Q. Cron

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Correspondence to Randy Q. Cron.

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Funding and Conflicts of Interest

This work was partially supported by the Rheumatology Research Foundation’s Investigator Award (L.A.H.), National Institute of Arthritis and Musculoskeletal and Skin Diseases, P30 AR070253-01 and K08 AR073339-01 (L.A.H.). L.A.H. has received speaking fees from Swedish Orphan Biovitrum (Sobi) (< US$1000). R.Q.C.’s work was supported in part by grants from the Histiocytosis Association, the Center for Genomic Medicine at the University of Alabama at Birmingham & HudsonAlpha Institute for Biotechnology, and an investigator-initiated clinical trial funded by Sobi.

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Henderson, L.A., Cron, R.Q. Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Childhood Inflammatory Disorders: Diagnosis and Management. Pediatr Drugs 22, 29–44 (2020). https://doi.org/10.1007/s40272-019-00367-1

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  • DOI: https://doi.org/10.1007/s40272-019-00367-1

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