Understanding the spectrum of haemophagocytic lymphohistiocytosis: Update on diagnostic challenges and therapeutic options

British Journal of Haematology

Volumn 174, Issue 2, 2016, Pages 175-187

  Brisse, Ellen ^a   Matthys, Patrick ^a   Wouters, Carine H ^b  

^a REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

^b UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

Diagnosis; Haemophagocytic lymphohistiocytosis; Haemophagocytic syndrome; Macrophage activation syndrome; Treatment

Indexed keywords

ALEMTUZUMAB; BIOLOGICAL MARKER; BUSULFAN; CANAKINUMAB; CORTICOSTEROID; CYCLOPHOSPHAMIDE; CYCLOSPORIN A; DACLIZUMAB; DEXAMETHASONE; ETOPOSIDE; METHOTREXATE; METHYLPREDNISOLONE; PREDNISOLONE; PREDNISONE; THYMOCYTE ANTIBODY; TOCILIZUMAB;

ABNORMAL LABORATORY RESULT; ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION; CLINICAL EFFECTIVENESS; CLINICAL FEATURE; CYTOKINE STORM; DISEASE ACTIVITY; DISEASE ASSOCIATION; DRUG EFFICACY; DRUG RESPONSE; HEMOPHAGOCYTIC SYNDROME; HUMAN; MOLECULAR PATHOLOGY; NONHUMAN; OUTCOME ASSESSMENT; PLASMAPHERESIS; PRACTICE GUIDELINE; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SPECTRUM; TREATMENT RESPONSE;

EID: 84978137607     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.14144     Document Type: Review

References (104)

1. Akashi, K., Hayashi, S., Gondo, H., Mizuno, S., Harada, M., Tamura, K., Yamasaki, K., Shibuya, T., Uike, N., Okamura, T., Miyamoto, T. & Niho, Y. (1994) Involvement of interferon-γ and macrophage colony-stimulating factor in pathogenesis of haemophagocytic lymphohistiocytosis in adults. British Journal of Haematology, 87, 243–250.
2. Aricò, M., Danesino, C., Pende, D. & Moretta, L. (2001) Pathogenesis of haemophagocytic lymphohistiocytosis. British Journal of Haematology, 114, 761–769.
3. Avcin, T., Tse, S.M.L., Schneider, R., Ngan, B. & Silverman, E.D. (2006) Macrophage activation syndrome as the presenting manifestation of rheumatic diseases in childhood. Journal of Pediatrics, 148, 683–686.
4. Bay, A., Coskun, E., Oztuzcu, S., Ergun, S., Yilmaz, F. & Aktekin, E. (2013) Evaluation of the plasma micro RNA expression levels in secondary hemophagocytic lymphohistiocytosis. Mediterranean Journal of Hematology and Infectious Diseases, 5, e2013066.
5. Beer, T. & Vadakara, J. (2015) Etiologies and short-term mortality in patients with ultraelevated serum ferritin. Southern Medical Journal, 108, 574–578.
6. Bode, S.F.N., Ammann, S., Al-Herz, W., Bataneant, M., Dvorak, C.C., Gehring, S., Gennery, A., Gilmour, K.C., Gonzalez-Granado, L.I., GroB-Wieltsch, U., Ifversen, M., Lingman-Framme, J., Matthes-Martin, S., Mesters, R., Meyts, I., vanMontfrans, J.M., Pachlopnik Schmid, J., Pai, S.-Y., Soler-Palacin, P., Schuermann, U., Schuster, V., Seidel, M.G., Speckmann, C., Stepensky, P., Sykora, K.W., Tesi, B., Vraetz, T., Waruiru, C., Bryceson, Y.T., Moshous, D., Lehmberg, K., Jordan, M.B. & Ehl, S.; on behalf of the Inborn Errors Working Party of the EBMT. (2015) The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis. Haematologica, 100, 978–988.
7. Bracaglia, C., Marafon, D., Caiello, I., de Graaf, K., Guilhot, F., Ferlin, W., Davì, S., Schulert, G., Ravelli, A., Grom, A., Nelson, R., de Min, C. & De Benedetti, F. (2015) High levels of interferon-gamma (IFNγ) in macrophage activation syndrome (MAS) and CXCL9 levels as a biomarker for IFNγ production in MAS. Pediatric Rheumatology, 13, O84.
8. Brisse, E., Wouters, C.H. & Matthys, P. (2015) Hemophagocytic lymphohistiocytosis (HLH): a heterogeneous spectrum of cytokine-driven immune disorders. Cytokine & Growth Factor Reviews, 26, 263–280.
9. Brito-Zerón, P., Bosch, X., Pérez-de-Lis, M., Pérez-Álvarez, R., Fraile, G., Gheitasi, H., Retamozo, S., Bové, A., Monclús, E., Escoda, O., Moreno, A., López-Guillermo, A., Khamashta, M.A. & Ramos-Casals, M. (2016) Infection is the major trigger of hemophagocytic syndrome in adult patients treated with biological therapies. Seminars in Arthritis and Rheumatism, 45, 391–399.
10. Bryceson, Y.T., Pende, D., Maul-Pavicic, A., Gilmour, K.C., Ufheil, H., Vraetz, T., Chiang, S.C., Marcenaro, S., Meazza, R., Bondzio, I., Walshe, D., Janka, G., Lehmberg, K., Beutel, K., Stadt, U.Zur, Binder, N., Arico, M., Moretta, L., Henter, J.I. & Ehl, S. (2012) A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood, 119, 2754–2763.
11. Canna, S.W. & Behrens, E.M. (2012) Not all hemophagocytes are created equally : appreciating the heterogeneity of the hemophagocytic syndromes. Current Opinion in Rheumatology, 24, 113–118.
12. Canna, S.W., Costa-reis, P., Bernal, W.E., Chu, N., Sullivan, K., Paessler, M. & Behrens, E.M. (2014) Alternative activation of laser-captured murine hemophagocytes. Arthritis & Rheumatism, 66, 1666–1671.
13. Carmo, M., Risma, K.A., Arumugam, P., Tiwari, S., Hontz, A.E., Montiel-Equihua, C.A., Alonso-Ferrero, M.E., Blundell, M.P., Schambach, A., Baum, C., Malik, P., Thrasher, A.J., Jordan, M.B. & Gaspar, H.B. (2014) Perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency. Molecular Therapy, 23, 737–745.
14. Castillo, L. & Carcillo, J. (2009) Secondary hemophagocytic lymphohistiocytosis and severe sepsis/systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatric Critical Care Medicine, 10, 387–92.
15. Cetica, V., Sieni, E., Pende, D., Danesino, C., De Fusco, C., Locatelli, F., Micalizzi, C., Putti, M.C., Biondi, A., Fagioli, F., Moretta, L., Griffiths, G.M., Luzzatto, L. & Aricò, M. (2016) Genetic predisposition to hemophagocytic lymphohistiocytosis: report on 500 patients from the Italian registry. The Journal of Allergy and Clinical Immunology, 137, 188–196.
16. Chen, J., Wang, X., He, P., Li, Y., Si, M., Fan, Z., Chang, X., Xie, Q. & Jiao, X. (2016) Viral etiology, clinical and laboratory features of adult hemophagocytic lymphohistiocytosis. Journal of Medical Virology, 88, 541–549.
17. Chiossone, L., Audonnet, S., Chetaille, B., Chasson, L., Farnarier, C., Berda-Haddad, Y., Jordan, S., Koszinowski, U.H., Dalod, M., Mazodier, K., Novick, D., Dinarello, C.A., Vivier, E. & Kaplanski, G. (2012) Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein. Frontiers in Immunology, 3, 239.
18. Chuang, H.-C., Lay, J.-D., Hsieh, W.-C. & Su, I.-J. (2007) Pathogenesis and mechanism of disease progression from hemophagocytic lymphohistiocytosis to Epstein-Barr virus-associated T-cell lymphoma: nuclear factor-kappa B pathway as a potential therapeutic target. Cancer Science, 98, 1281–7.
19. Cifaldi, L., Prencipe, G., Caiello, I., Bracaglia, C., Locatelli, F., De Benedetti, F. & Strippoli, R. (2015) Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis & Rheumatology, 67, 3037–46.
20. Créput, C., Galicier, L., Buyse, S. & Azoulay, E. (2008) Understanding organ dysfunction in hemophagocytic lymphohistiocytosis. Intensive Care Medicine, 34, 1177–87.
21. Das, R., Guan, P., Sprague, L., Verbist, K., Tedrick, P., An, Q.A., Cheng, C., Kurachi, M., Levine, R., Wherry, J., Canna, S.W., Behrens, E.M. & Nichols, K.E. (2016) Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood, 127, 1666–1675.
22. Davì, S., Consolaro, A., Guseinova, D., Pistorio, A., Ruperto, N., Martini, A., Cron, R.Q. & Ravelli, A. (2011) An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. The Journal of Rheumatology, 38, 764–8.
23. Davì, S., Minoia, F., Pistorio, A., Horne, A., Consolaro, A., Rosina, S., Bovis, F., Cimaz, R., Gamir, M.L., Ilowite, N.T., Kone-Paut, I., Feitosa de Oliveira, S.K., McCurdy, D., Silva, C.A., Sztajnbok, F., Tsitsami, E., Unsal, E., Weiss, J.E., Wulffraat, N., Abinun, M., Aggarwal, A., Apaz, M.T., Astigarraga, I., Corona, F., Cuttica, R., D'Angelo, G., Eisenstein, E.M., Hashad, S., Lepore, L., Mulaosmanovic, V., Nielsen, S., Prahalad, S., Rigante, D., Stanevicha, V., Sterba, G., Susic, G., Takei, S., Trauzeddel, R., Zletni, M., Ruperto, N., Martini, A., Cron, R.Q. & Ravelli, A. (2014) Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthritis & Rheumatology, 66, 2871–80.
24. Emmenegger, U., Zehnder, R., Frey, U., Reimers, A., Spaeth, P.J. & Neftel, K.A. (2000) Elevation of soluble Fas and soluble Fas ligand in reactive macrophage activation syndromes. American Journal of Hematology, 64, 116–119.
25. Fardet, L., Galicier, L. & Lambotte, O. (2014) Development and validation of a score for the diagnosis of reactive hemophagocytic syndrome (HScore). Arthritis & Rheumatism, 66, 2613–20.
26. Fisman, D.N. (2000) Hemophagocytic syndromes and infection. Emerging Infectious Diseases, 6, 601–8.
27. Gorelik, M., Fall, N., Altaye, M., Barnes, M.G., Thompson, S.D., Grom, A.A. &Hirsch, R. (2013) 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. The Journal of Rheumatology, 40, 1191–9.
28. Grom, A.A. (2004) Natural killer cell dysfunction: a common pathway in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis? Arthritis and Rheumatism, 50, 689–98.
29. Grom, A.A., Ilowite, N.T., Pascual, V., Brunner, H.I., Martini, A., Lovell, D., Ruperto, N., Leon, K., Lheritier, K. & Abrams, K. (2016) Canakinumab in systemic juvenile idiopathic arthritis: impact on the rate and clinical presentation of macrophage activation syndrome. Arthritis & Rheumatology, 68, 218–228.
30. Henter, J.I., Horne, A., Arico, M., Egeler, R.M., Webb, D., Winiarski, J. & Janka, G. (2007) HLH-2004 : diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pedriatric Blood & Cancer, 12, 4–131.
31. Hibi, S., Ikushima, S., Fujiwara, F., Hashida, T., Tsunamoto, K., Todo, S. & Imashuku, S. (1995) Serum and urine beta-2-microglobulin in hemophagocytic syndrome. Cancer, 75, 1700–5.
32. Holzinger, D., Fall, N., Grom, A., de Jager, W., Vastert, S., Strippoli, R., Bracaglia, C., Sundberg, E., Horne, A., Ehl, S., De Benedetti, F., Beutel, K. & Foell, D. (2015) S100A12 as diagnostic tool in the differential diagnosis of sJIA associated MAS vs. hereditary or acquired HLH. Pediatric Rheumatology, 13, O64.
33. Horne, A., Janka, G., Egeler, R.M., Gadner, H., Imashuku, S., Ladisch, S., Locatelli, F., Montgomery, S.M., Webb, D., Winiarski, J., Filipovich, A.H. & Henter, J.I. (2005) Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis. British Journal of Haematology, 129, 622–630.
34. Horne, A., Trottestam, H., Aricò, M., Egeler, R.M., Filipovich, A.H., Gadner, H., Imashuku, S., Ladisch, S., Webb, D., Janka, G. & Henter, J.I. (2008) Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. British Journal of Haematology, 140, 327–335.
35. Hsieh, W.-C., Lan, B.-S., Chen, Y.-L., Chang, Y., Chuang, H.-C. & Su, I.-J. (2010) Efficacy of peroxisome proliferator activated receptor agonist in the treatment of virus-associated haemophagocytic syndrome in a rabbit model. Antiviral Therapy, 15, 71–81.
36. Ibarra, M.F., Klein-Gitelman, M., Morgan, E., Proytcheva, M., Sullivan, C., Morgan, G., Pachman, L.M. & O'Gorman, M.R.G. (2011) Serum neopterin levels as a diagnostic marker of hemophagocytic lymphohistiocytosis syndrome. Clinical and Vaccine Immunology, 18, 609–14.
37. Ishii, E., Ohga, S., Imashuku, S., Yasukawa, M., Tsuda, H., Miura, I., Yamamoto, K., Horiuchi, H., Takada, K., Ohshima, K., Nakamura, S., Kinukawa, N., Oshimi, K. & Kawa, K. (2007) Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. International Journal of Hematology, 86, 58–65.
38. Janka, G.E. (2007) Familial and acquired hemophagocytic lymphohistiocytosis. European Journal of Pediatrics, 166, 95–109.
39. Janka, G.E. & Lehmberg, K. (2013) Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology/the Education Program of the American Society of Hematology, 2013, 605–611.
40. Janka, G.E. & Lehmberg, K. (2014) Hemophagocytic syndromes - an update. Blood Reviews, 28, 135–142.
41. Jenkins, R.W., Clarke, C.J., Lucas, J.T., Shabbir, M., Wu, B.X., Simbari, F., Mueller, J., Hannun, Y.A., Lazarchick, J. &Shirai, K. (2013) Evaluation of the role of secretory sphingomyelinase and bioactive sphingolipids as biomarkers in hemophagocytic lymphohistiocytosis. American Journal of Hematology, 88, E265–72.
42. Johnson, T.S., Terrell, C.E., Millen, S.H., Katz, J.D., Hildeman, D.A. & Jordan, M.B. (2014) Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. The Journal of Immunology, 192, 84–91.
43. Jordan, M.B., Allen, C.E., Weitzman, S., Filipovich, A.H. & McClain, K.L. (2011) How I treat hemophagocytic lymphohistiocytosis. Blood, 118, 4041–52.
44. Jordan, M., Locatelli, F., Allen, C., De Benedetti, F., Grom, A.A., Ballabio, M., Ferlin, W.G., NI-0501-04 Study Group & De Min, C. (2015) 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, 126, LBA–3.
45. Kahn, P.J. & Cron, R.Q. (2013) Higher-dose anakinra is effective in a case of medically refractory macrophage activation syndrome the journal of rheumatology is a monthly international serial edited by Earl D. Silverman featuring research articles on clinic. The Journal of Rheumatology, 40, 5–7.
46. Kobayashi, M., Takahashi, Y., Yamashita, H., Kaneko, H. & Mimori, A. (2011) Benefit and a possible risk of tocilizumab therapy for adult-onset Still's disease accompanied by macrophage-activation syndrome. Modern Rheumatology/the Japan Rheumatism Association, 21, 92–6.
47. Kobayashi, R., Tanaka, J., Hashino, S., Ota, S., Torimoto, Y., Kakinoki, Y., Yamamoto, S., Kurosawa, M., Hatakeyama, N., Haseyama, Y., Sakai, H., Sato, K. & Fukuhara, T. (2014) Etoposide-containing conditioning regimen reduces the occurrence of hemophagocytic lymphohistiocytosis after SCT. Bone Marrow Transplantation, 49, 254–7.
48. Koorts, A.M. & Viljoen, M. (2011) Acute phase proteins: ferritin and ferritin isoforms. In: Acute Phase Proteins - Regulation and Functions of Acute Phase Proteins (ed. by F. Veas), pp. 153–184. InTech: Rijeka, Croatia.
49. Kostik, M.M., Dubko, M.F., Masalova, V.V., Snegireva, L.S., Kornishina, T.L., Chikova, I.A., Likhacheva, T.S., Isupova, E.A., Glebova, N.I., Kuchinskaya, E.M., Balbotkina, E.V., Buchinskaya, N.V., Kalashnikova, O.V. & Chasnyk, V.G. (2015) Identification of the best cutoff points and clinical signs specific for early recognition of macrophage activation syndrome in active systemic juvenile idiopathic arthritis. Seminars in Arthritis and Rheumatism, 44, 417–22.
50. Kuriyama, T., Takenaka, K., Kohno, K., Yamauchi, T., Daitoku, S., Yoshimoto, G., Kikushige, Y., Kishimoto, J., Abe, Y., Harada, N., Miyamoto, T., Iwasaki, H., Teshima, T. & Akashi, K. (2012) Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis. Blood, 120, 4058–67.
51. Lehmberg, K., Pink, I., Eulenburg, C., Beutel, K., Maul-Pavicic, A. & Janka, G. (2013) Differentiating macrophage activation syndrome in systemic juvenile idiopathic arthritis from other forms of hemophagocytic lymphohistiocytosis. The Journal of Pediatrics, 162, 1245–51.
52. Lehmberg, K., Mcclain, K.L., Janka, G.E. & Allen, C.E. (2014) Determination of an appropriate cut-off value for ferritin in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatric Blood & Cancer, 61, 2101–3.
53. Lehmberg, K., Nichols, K.E., Henter, J.-I., Girschikofsky, M., Greenwood, T., Jordan, M., Kumar, A., Minkov, M., La Rosée, P. & Weitzman, S.; Study Group on Hemophagocytic Lymphohistiocytosis Subtypes of the Histiocyte Society (2015) Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica, 100, 997–1004.
54. Maruoka, H., Inoue, D., Takiuchi, Y., Nagano, S., Arima, H., Tabata, S., Matsushita, A., Ishikawa, T., Oita, T. & Takahashi, T. (2014) IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-associated hemophagocytic syndrome. Annals of Hematology, 93, 393–401.
55. Maruyama, J. & Inokuma, S. (2010) Cytokine profiles of macrophage activation syndrome associated with rheumatic diseases. The Journal of Rheumatology, 37, 967–73.
56. Mazodier, K., Marin, V., Novick, D., Farnarier, C., Robitail, S., Schleinitz, N., Veit, V., Paul, P., Rubinstein, M., Dinarello, C.A., Harlé, J.-R. & Kaplanski, G. (2005) Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood, 106, 3483–9.
57. McCoy, M.W., Moreland, S.M. & Detweiler, C.S. (2012) Hemophagocytic macrophages in murine typhoid fever have an anti-inflammatory phenotype. Infection and Immunity, 80, 3642–9.
58. Meeths, M., Horne, A., Sabel, M., Bryceson, Y.T. & Henter, J.-I. (2015) Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden. Pediatric Blood & Cancer, 62, 346–352.
59. Niece, J.A., Roger, Z.R., Ahmad, N., Langevin, A.-M. & McClain, K.L. (2010) Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatric Blood & Cancer, 54, 424–428.
60. Nigrovic, P.A., Mannion, M., Prince, F.H.M., Zeft, A., Rabinovich, C.E., van Rossum, M.A.J., Cortis, E., Pardeo, M., Miettunen, P.M., Janow, G., Birmingham, J., Eggebeen, A., Janssen, E., Shulman, A.I., Son, M.B., Hong, S., Jones, K., Ilowite, N.T., Cron, R.Q. & Higgins, G.C. (2011) Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis and Rheumatism, 63, 545–55.
61. Nold-Petry, C.A., Lehrnbecher, T., Jarisch, A., Schwabe, D., Pfeilschifter, J.M., Muhl, H. & Nold, M.F. (2010) Failure of interferon gamma to induce the anti-inflammatory interleukin 18 binding protein in familial hemophagocytosis. PLoS ONE, 5, e8663.
62. Ohga, S., Nomura, A., Kai, T., Matsuzaki, A., Inaba, S., Suda, M. & Ueda, K. (1997) Case report prolonged resolution of hemophagocytic lymphohistiocytosis following myeloablative chemotherapy and subsequent autologous peripheral blood stem cell transplantation. Bone Marrow Transplantation, 19, 633–635.
63. Olin, R.L., Nichols, K.E., Naghashpour, M., Wasik, M., Shelly, B., Stadtmauer, E.A. & Vogl, D.T. (2008) Successful use of the anti-CD25 antibody daclizumab in an adult patient with hemophagocytic lymphohistiocytosis. American Journal of Hematology, 83, 747–749.
64. Osugi, Y., Hara, J., Tagawa, S., Takai, K., Hosoi, G., Matsuda, Y., Ohta, H., Fujisaki, H., Kobayashi, M., Sakata, N., Kawa-Ha, K., Okada, S. & Tawa, A. (1997) Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood, 89, 4100–3.
65. Ozen, S., Dai, A., Coskun, E., Oztuzcu, S., Ergun, S., Aktekin, E., Yavuz, S. & Bay, A. (2014) Importance of hyperbilurubinemia in differentiation of primary and secondary hemophagocytic lymphohistiocytosis in pediatric cases. Mediterranean Journal of Hematology and Infectious Diseases, 6, e2014067.
66. Palmblad, K., Schierbeck, H., Sundberg, E., Horne, A.-C., Harris, H.E., Henter, J.-I., Antoine, D.J. & Andersson, U. (2014) High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome. Molecular Medicine, 20, 538–47.
67. Parodi, A., Davì, S., Pringe, A.B., Pistorio, A., Ruperto, N., Magni-Manzoni, S., Miettunen, P., Bader-Meunier, B., Espada, G., Sterba, G., Ozen, S., Wright, D., Magalhães, C.S., Khubchandani, R., Michels, H., Woo, P., Iglesias, A., Guseinova, D., Bracaglia, C., Hayward, K., Wouters, C., Grom, A., Vivarelli, M., Fischer, A., Breda, L., Martini, A. & Ravelli, A.; on behalf of the Lupus Working Group of the Paediatric Rheumatology European Society. (2009) Macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients. Arthritis and Rheumatism, 60, 3388–99.
68. Put, K., Avau, A., Brisse, E., Mitera, T., Put, S., Proost, P., Bader-Meunier, B., Westhovens, R., Van den Eynde, B.J., Orabona, C., Fallarino, F., De Somer, L., Tousseyn, T., Quartier, P., Wouters, C. & Matthys, P. (2015) Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ. Rheumatology, 54, 1507–1517.
69. Rajasekaran, S., Kruse, K., Kovey, K., Davis, A.T., Hassan, N.E., Ndika, A.N., Zuiderveen, S. & Birmingham, J. (2014) 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. Pediatric Critical Care Medicine, 15, 401–8.
70. Ramos-Casals, M., Brito-Zerón, P., López-Guillermo, A., Khamashta, M.A. & Bosch, X. (2014) Adult haemophagocytic syndrome. Lancet, 383, 1503–16.
71. Ravelli, A., Magni-Manzoni, S., Pistorio, A., Besana, C., Foti, T., Ruperto, N., Viola, S. & Martini, A. (2005) Preliminary diagnostic guidelines for macrophage activation syndrome complications systemic juvenile idiopathic arthritis. Journal of Pediatrics, 146, 598–604.
72. Ravelli, A., Minoia, F., Davì, S., Horne, A., Bovis, F., Pistorio, A., Aricò, M., Avcin, T., Behrens, E.M., De Benedetti, F., Filipovic, L., Grom, A.A., Henter, J.-I., Ilowite, N.T., Jordan, M.B., Khubchandani, R., Kitoh, T., Lehmberg, K., Lovell, D.J., Miettunen, P., Nichols, K.E., Ozen, S., Pachlopnik Schmid, J., Ramanan, A.V., Russo, R., Schneider, R., Sterba, G., Uziel, Y., Wallace, C., Wouters, C., Wulffraat, N., Demirkaya, E., Brunner, H.I., Martini, A., Ruperto, N. & Cron, R.Q. (2016a) 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Annals of the Rheumatic Diseases, 75, 481–489.
73. Ravelli, A., Minoia, F., Davì, S., Horne, A., Bovis, F., Pistorio, A., Aricò, M., Avcin, T., Behrens, E.M., De Benedetti, F., Filipovic, A., Grom, A.A., Henter, J.-I., Ilowite, N.T., Jordan, M.B., Khubchandani, R., Kitoh, T., Lehmberg, K., Lovell, D.J., Miettunen, P., Nichols, K.E., Ozen, S., Pachlopnik Schmid, J., Ramanan, A.V., Russo, R., Schneider, R., Sterba, G., Uziel, Y., Wallace, C., Wouters, C., Wulffraat, N., Demirkaya, E., Brunner, H., Martini, A., Ruperto, N. & Cron, R.Q. (2016b) Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. RMD Open, 2, e000161.
74. Reinhardt, R.L., Liang, H.-E., Bao, K., Price, A.E., Mohrs, M., Kelly, B.L. & Locksley, R.M. (2015) A novel model for IFN-gamma-mediated autoinflammatory syndromes. The Journal of Immunology, 194, 2358–2368.
75. Rivat, C., Booth, C., Alonso-Ferrero, M., Blundell, M., Sebire, N.J., Thrasher, A.J. & Gaspar, H.B. (2013) SAP gene transfer restores cellular and humoral immune function in a murine model of X-linked lymphoproliferative disease. Blood, 121, 1073–6.
76. Rood, J.E., Rao, S., Paessler, M., Kreiger, P.A., Chu, N., Stelekati, E., Wherry, E.J. & Behrens, E.M. (2016) ST2 contributes to T cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice. Blood, 127, 426–435.
77. Rouphael, N.G., Talati, N.J., Vaughan, C., Cunningham, K., Moreira, R. & Gould, C. (2007) Infections associated with haemophagocytic syndrome. The Lancet. Infectious Diseases., 7, 814–822.
78. Ruscitti, P., Cipriani, P., Di Benedetto, P., Ciccia, F., Liakouli, V., Carubbi, F., Berardicurti, O., Rizzo, A., Triolo, G. & Giacomelli, R. (2015) Increased level of H-ferritin and its imbalance with L-ferritin, in bone marrow and liver of patients with adult onset Still's disease, developing macrophage activation syndrome, correlate with the severity of the disease. Autoimmunity Reviews, 14, 429–437.
79. Saeed, H., Woods, R.R., Lester, J., Herzig, R., Gul, Z. & Monohan, G. (2015) Evaluating the optimal serum ferritin level to identify hemophagocytic lymphohistiocytosis in the critical care setting. International Journal of Hematology, 102, 195–199.
80. Schaer, D.J., Schleiffenbaum, B., Kurrer, M., Imhof, A., Bächli, E., Fehr, J., Moller, H.J., Moestrup, S.K. & Schaffner, A. (2005) Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome. European Journal of Haematology, 74, 6–10.
81. Schulert, G.S. & Grom, A.A. (2015) Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annual Review of Medicine, 66, 145–159.
82. Scott, R. & Robb-Smith, A. (1939) Histiocytic medullary reticulocytosis. Lancet, 2, 194–198.
83. Shimazaki, C., Inaba, T. & Nakagawa, M. (2000) B-cell lymphoma-associated hemophagocytic syndrome. Leukemia & Lymphoma, 38, 121–30.
84. Shimizu, M., Yokoyama, T., Yamada, K., Kaneda, H., Wada, H., Wada, T., Toma, T., Ohta, K., Kasahara, Y. & Yachie, A. (2010) 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, 49, 1645–53.
85. Shimizu, M., Nakagishi, Y., Kasai, K., Yamasaki, Y., Miyoshi, M., Takei, S. & Yachie, A. (2012) Tocilizumab masks the clinical symptoms of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: the diagnostic significance of interleukin-18 and interleukin-6. Cytokine, 58, 287–94.
86. Shimizu, M., Nakagishi, Y., Inoue, N., Mizuta, M., Ko, G., Saikawa, Y., Kubota, T., Yamasaki, Y., Takei, S. & Yachie, A. (2015) Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Clinical Immunology, 160, 277–281.
87. Takahashi, N., Chubati, A., Miura, I., Nakamura, S. & Miura, T. (1999) Lymphoma-associated hemophagocytic syndrome in Japan. Japanese Journal of Clinical Hematology, 40, 542–549 [in Japanese, abstract in English].
88. Tamura, K., Kanazawa, T., Tsukada, S., Kobayashi, T., Kawamura, M. & Morikawa, A. (2008) Increased serum monocyte chemoattractant protein-1, macrophage inflammatory protein-1 beta, and interleukin-8 concentration in hemophagocytic lymphohistiocytosis. Pediatric Blood & Cancer, 51, 662–668.
89. Terrell, C.E. & Jordan, M.B. (2013) Mixed hematopoietic or T cell chimerism above a minimal threshold restores perforin-dependent immune regulation in perforin-deficient mice. Blood, 122, 2618–21.
90. Teruya-Feldstein, J., Setsuda, J., Yao, X., Kingma, D.W., Straus, S., Tosato, G. & Jaffe, E.S. (1999) MIP-1alpha expression in tissues from patients with hemophagocytic syndrome. Laboratory Investigation, 79, 1583–90.
91. Toga, A., Wada, T., Sakakibara, Y., Mase, S., Araki, R., Tone, Y., Toma, T., Kurokawa, T., Yanagisawa, R., Tamura, K., Nishida, N., Taneichi, H., Kanegane, H. & Yachie, A. (2010) Clinical Significance of Cloned Expansion and CD5 Down-Regulation in Epstein-Barr Virus (EBV)–Infected CD8 + T Lymphocytes in EBV-Associated Hemophagocytic Lymphohistiocytosis. The Journal of Infectious Diseases, 201, 1923–1932.
92. Valade, S., Azoulay, E., Galicier, L., Boutboul, D., Zafrani, L., Stepanian, A., Canet, E., Lemiale, V., Venot, M., Veyradier, A. & Mariotte, E. (2015) Coagulation Disorders and Bleedings in Critically Ill Patients With Hemophagocytic Lymphohistiocytosis. Medicine, 94, e1692.
93. Wada, T., Muraoka, M., Yokoyama, T., Toma, T., Kanegane, H. & Yachie, A. (2013) Cytokine Profiles in Children With Primary Epstein – Barr Virus Infection. Pediatric Blood & Cancer, 60, E46–E48.
94. Wada, T., Yasumi, T., Toma, T., Hori, M., Maeda, S., Umeda, K., Heike, T., Adachi, S., Usami, I. & Yachie, A. (2014) Munc13-4 deficiency with CD5 downregulation on activated CD8 + T cells. Pediatrics International, 56, 605–8.
95. Wang, Z., Wang, Y., Wang, J., Feng, C., Tian, L. & Wu, L. (2009) Early diagnostic value of low percentage of glycosylated ferritin in secondary hemophagocytic lymphohistiocytosis. International Journal of Hematology, 90, 501–5.
96. Wang, Y., Huang, W., Hu, L., Cen, X., Li, L., Wang, J., Shen, J., Wei, N. & Wang, Z. (2015) Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. Blood, 126, 2186–2193.
97. Weaver, L.K. & Behrens, E.M. (2014) Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Current Opinion in Rheumatology, 26, 562–9.
98. Wulffraat, N.M. (2003) Reduced perforin expression in systemic juvenile idiopathic arthritis is restored by autologous stem-cell transplantation. Rheumatology, 42, 375–379.
99. Yasumi, T., Hori, M., Hiejima, E., Shibata, H., Izawa, K., Oda, H., Yoshioka, K., Nakagawa, K., Kawai, T., Nishikomori, R., Ohara, O. & Heike, T. (2015) Laboratory parameters identify familial haemophagocytic lymphohistiocytosis from other forms of paediatric haemophagocytosis. British Journal of Haematology, 170, 532–538.
100. Yokota, S., Itoh, Y., Morio, T., Origasa, H., Sumitomo, N., Tomobe, M., Tanaka, K. & Minota, S. (2015) Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting : results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan. Annals of Rheumatic Disease, doi:10.1136/annrheumdis-2015-207818 [Epub ahead of print].
101. Zhang, K., Jordan, M.B., Marsh, R.A., Johnson, J.A., Kissell, D., Meller, J., Villanueva, J., Risma, K.A., Wei, Q., Klein, P.S. & Filipovich, A.H. (2011) Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood, 118, 5794–5798.
102. Zhang, M., Behrens, E.M., Atkinson, T.P., Shakoory, B., Grom, A.A. & Cron, R.Q. (2014) Genetic defects in cytolysis in macrophage activation syndrome. Current Rheumatology Reports, 16, 439–446.
103. Zhou, C., Xie, Z., Gao, L., Liu, C., Ai, J. & Zhang, L. (2015) Profiling of EBV-Encoded microRNAs in EBV-Associated Hemophagocytic Lymphohistiocytosis. Tohoku Journal of Experimental Medicine, 237, 117–126.
104. Zoller, E.E., Lykens, J.E., Terrell, C.E., Aliberti, J., Filipovich, A.H., Henson, P.M. & Jordan, M.B. (2011) Hemophagocytosis causes a consumptive anemia of inflammation. The Journal of Experimental Medicine, 208, 1203–1214.