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TRENDS IN MOLECULAR MEDICINE

Hemophagocytic lymphohistiocytosis: Diagnosis, pathophysiology, treatment, and future perspectives

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Pages 20-31 | Published online: 08 Jul 2009

References

  • Henter J. I., Elinder G., Soder O., Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scan 1991; 80: 428–35
  • Henter J. I., Arico M., Elinder G., Imashuku S., Janka G. Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998; 12: 417–33
  • Henter J. I., Elinder G., Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol 1991; 18: 29–33
  • Arico M., Janka G., Fischer A., Henter J. I., 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: 197–203
  • Dufourcq‐Lagelouse R., Pastural E., Barrat F. J., Feldmann J., Le Deist F., Fischer A., et al. Genetic basis of hemophagocytic lymphohistiocytosis syndrome (Review). Int J Mol Med 1999; 4: 127–33
  • Perez N., Virelizier J. L., Arenzana‐Seisdedos F., Fischer A., Griscelli C. Impaired natural killer activity in lymphohistiocytosis syndrome. J Pediatr 1984; 104: 569–73
  • Arico M., Nespoli L., Maccario R., Montagna D., Bonetti F., Caselli D., et al. Natural cytotoxicity impairment in familial haemophagocytic lymphohistiocytosis. Arch Dis Child 1988; 63: 292–6
  • Sullivan K. E., Delaat C. A., Douglas S. D., Filipovich A. H. Defective natural killer cell function in patients with hemophagocytic lymphohistiocytosis and in first degree relatives. Pediatr Res 1998; 44: 465–8
  • Group HLS. HLH‐2004: Treatment Protocol of the Second International HLH Study 2004. 2004. (http://histio.org/society/protocols/trials‐protocols.shtml).
  • Henter J. I., Elinder G. Cerebromeningeal haemophagocytic lymphohistiocytosis. [see comment]. Lancet 1992; 339: 104–7
  • Allen M., De Fusco C., Legrand F., Clementi R., Conter V., Danesino C., et al. Familial hemophagocytic lymphohistiocytosis: how late can the onset be?. Haematologica 2001; 86: 499–503
  • Ishii E., Ueda I., Shirakawa R., Horiuchi H., Ohga S., Furuno K., et al. Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood 2005; 105: 3442–8
  • Clementi R., Emmi L., Maccario R., Liotta F., Moretta L., Danesino C., et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood 2002; 100: 2266–7
  • Janka G., Imashuku S., Elinder G., Schneider M., Henter J. I. Infection‐ and malignancy‐associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998; 12: 435–44
  • Imashuku S., Hibi S., Tabata Y., Sako M., Sekine Y., Hirayama K., et al. Biomarker and morphological characteristics of Epstein‐Barr virus‐related hemophagocytic lymphohistiocytosis. Med Pediatr Oncol 1998; 31: 131–7
  • Imashuku S., Tabata Y., Teramura T., Hibi S. Treatment strategies for Epstein‐Barr virus‐associated hemophagocytic lymphohistiocytosis (EBV‐HLH). Leuk Lymphoma 2000; 39: 37–49
  • Stepp S. E., Dufourcq‐Lagelouse R., Le Deist F., Bhawan S., Certain S., Mathew P. A., et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999; 286: 1957–9
  • Masson D., Tschopp J. Isolation of a lytic, pore‐forming protein (perforin) from cytolytic T‐lymphocytes. J Biol Chem 1985; 260: 9069–72
  • Catalfamo M., Henkart P. A. Perforin and the granule exocytosis cytotoxicity pathway. Curr Opin Immunol 2003; 15: 522–7
  • Raja S. M., Metkar S., Froehlich J. Cytotoxic granule‐mediated apoptosis: unraveling the complex mechanism. Curr Opin Immunol 2003; 15: 528–32
  • Lieberman J. The ABCs of granule‐mediated cytotoxicity: new weapons in the arsenal. Nature Rev Immunol 2003; 3: 361–70
  • Young J. D., Cohn Z. A., Podack E. R. The ninth component of complement and the pore‐forming protein (perforin 1) from cytotoxic T cells: structural, immunological, and functional similarities. Science 1986; 233: 184–90
  • Russell J. H., Ley T. J. Lymphocyte‐mediated cytotoxicity. Annu Rev Immunol 2002; 20: 323–70
  • Grossman W. J., Revell P. A., Lu Z. H., Johnson H. J., Bredemeyer A. J., Ley T. J. The orphan granzymes of humans and mice. Curr Opin Immunol 2003; 15: 544–42
  • Kogawa K., Lee S. M., Villanueva J., Marmer D., Sumegi J., Filipovich A. H. Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members. Blood 2002; 99: 61–6
  • Ueda I., Morimoto A., Inaba T., Yagi T., Hibi S., Sugimoto T., et al. Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan. Br J Haematol 2003; 121: 503–10
  • Ishii E., Ohga S., Tanimura M., Imashuku S., Sako M., Mizutani S., et al. Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan. Japan LCH Study Group. Med Pediatr Oncol 1998; 30: 276–83
  • Molleran Lee S., Villanueva J., Sumegi J., Zhang K., Kogawa K., Davis J., et al. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet 2004; 41: 137–44
  • Feldman 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: 461–73
  • Neeft M., Wieffer M., de Jong A. S., Negroiu G., Metz C. H., van Loon A., et al. Munc13‐4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells. Mol Biol Cell 2005; 16: 731–41
  • Rothman J. E. Lasker Basic Medical Research Award. The machinery and principles of vesicle transport in the cell. Nat Med 2002; 8: 1059–62
  • Purtilo D. T., Cassel C. K., Yang J. P., Harper R. X‐linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet 1975; 1: 935–40
  • Hamilton J. K., Paquin L. A., Sullivan J. L., Maurer H. S., Cruzi F. G., Provisor A. J., et al. X‐linked lymphoproliferative syndrome registry report. J Pediatr 1980; 96: 669–73
  • Arico M., Imashuku S., Clementi R., Hibi S., Teramura T., Danesino C., et al. Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X‐linked lymphoproliferative disease gene. Blood 2001; 97: 1131–3
  • Latour S., Veillette A. Molecular and immunological basis of X‐linked lymphoproliferative disease. Immunol Rev 2003; 192: 212–24
  • Latour S., Veillette A. The SAP family of adaptors in immune regulation. Semin Immunol 2004; 16: 409–19
  • Veillette A., Latour S. The SLAM family of immune‐cell receptors. Curr Opin Immunol 2003; 15((3))277–85
  • Sharifi R., Sinclair J. C., Gilmour K. C., Arkwright P. D., Kinnon C., Thrasher A. J., et al. SAP mediates specific cytotoxic T‐cell functions in X‐linked lymphoproliferative disease. Blood 2004; 103: 3821–7
  • Gaspar H. B., Sharifi R., Gilmour K. C., Thrasher A. J. X‐linked lymphoproliferative disease: clinical, diagnostic and molecular perspective. Br J Haematol 2002; 119: 585–95
  • Klein C., Philippe N., Le Deist F., Fraitag S., Prost C., Durandy A., et al. Partial albinism with immunodeficiency (Griscelli syndrome). J Pediatr 1994; 125: 886–95
  • Pastural E., Ersoy F., Yalman N., Wulffraat N., Grillo E., Ozkinay F., et al. Two genes are responsible for Griscelli syndrome at the same 15q21 locus. Genomics 2000; 63: 299–306
  • Trambas C. M., Griffiths G. M. Delivering the kiss of death. Nat Immunol 2003; 4: 399–403
  • Stinchcombe J., Bossi G., Griffiths G. M. Linking albinism and immunity: The secrets of secretory lysosomes. Science 2004; 305: 55–59
  • Blott E. J., Griffiths G. M. Secretory lysosomes. Nat Rev Mol Cell Biol 2002; 3: 122–31
  • Pastural E., Barrat F. J., Dufourcq‐Lagelouse R., Certain S., Sanal O., Jabado N., et al. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin‐Va gene. [erratum appears in Nat Genet 1999 Nov;23(3):373]. Nat Genet 1997; 16: 289–92
  • 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: 173–6
  • Kumar M., Sackey K., Schmalstieg F., Trizna Z., Elghetany M. T., Alter B. P. Griscelli syndrome: rare neonatal syndrome of recurrent hemophagocytosis. J Pediatr Hematol Oncol 2001; 23: 464–8
  • Stinchcombe J. C., Barral D. C., Mules E. H., Booth S., Hume A. N., Machesky L. M., et al. Rab27a is required for regulated secretion in cytotoxic T lymphocytes. J Cell Biol 2001; 152: 825–34
  • Stinchcombe J. C., Page L. J., Griffiths G. M. Secretory lysosome biogenesis in cytotoxic T lymphocytes from normal and Chediak Higashi syndrome patients. Traffic 2000; 1: 435–44
  • Haddad E. K., Wu X., Hammer J. A 3rd., Henkart P. A. Defective granule exocytosis in Rab27a‐deficient lymphocytes from Ashen mice. [see comment]. J Cell Biol 2001; 152: 835–42
  • Blume R. S., Wolff S. M. The Chediak‐Higashi syndrome: studies in four patients and a review of the literature. Medicine 1972; 51: 247–80
  • Introne W., Boissy R. E., Gahl W. A. Clinical, molecular, and cell biological aspects of Chediak‐Higashi syndrome. Mol Genet Metab 1999; 68: 283–303
  • Rubin C. M., Burke B. A., McKenna R. W., McClain K. L., White J. G., Nesbit M. E., Jr, et al. The accelerated phase of Chediak‐Higashi syndrome. An expression of the virus‐associated hemophagocytic syndrome?. Cancer 1985; 56: 524–30
  • Haddad E., Le Deist F., Blanche S., Benkerrou M., Rohrlich P., Vilmer E., et al. Treatment of Chediak‐Higashi syndrome by allogenic bone marrow transplantation: report of 10 cases. Blood 1995; 85: 3328–33
  • Baetz K., Isaaz S., Griffiths G. M. Loss of cytotoxic T lymphocyte function in Chediak‐Higashi syndrome arises from a secretory defect that prevents lytic granule exocytosis. J Immunol 1995; 154: 6122–31
  • Barbosa M. D., Nguyen Q. A., Tchernev V. T., Ashley J. A., Detter J. C., Blaydes S. M., et al. Identification of the homologous beige and Chediak‐Higashi syndrome genes. [erratum appears in Nature 1997;385:97]. Nature 1996; 382: 262–5
  • Perou C. M., Moore K. J., Nagle D. L., Misumi D. J., Woolf E. A., McGrail S. H., et al. Identification of the murine beige gene by YAC complementation and positional cloning. Nat Genet 1996; 13: 303–8
  • Roder J. C., Haliotis T., Laing L., Kozbor D., Rubin P., Pross H., et al. Further studies of natural killer cell function in Chediak‐Higashi patients. Immunology 1982; 46: 555–60
  • Roder J. C. Characterization of a murine model (beige) for a natural killer cell immunodeficiency in the Chediak‐Higashi syndrome of man. Prog Clin Biol Res 1982; 94: 315–25
  • Haliotis T., Roder J., Klein M., Ortaldo J., Fauci A. S., Herberman R. B. Chediak‐Higashi gene in humans I. Impairment of natural‐killer function. J Exp Med 1980; 151: 1039–48
  • Ward D. M., Shiflett S. L., Kaplan J. Chediak‐Higashi syndrome: a clinical and molecular view of a rare lysosomal storage disorder. Curr Mol Med 2002; 2: 469–77
  • Sullivan K. E., Mullen C. A., Blaese R. M., Winkelstein J. A. A multiinstitutional survey of the Wiskott‐Aldrich syndrome. J Pediatr 1994; 125: 876–85
  • Imai K., Morio T., Zhu Y., Jin Y., Itoh S., Kajiwara M., et al. Clinical course of patients with WASP gene mutations. Blood 2004; 103: 456–64
  • Burns S., Cory G. O., Vainchenker W., Thrasher A. J. Mechanisms of WASp‐mediated hematologic and immunologic disease. Blood 2004; 104: 3454–62
  • Notarangelo L. D., Ochs H. D. Wiskott‐Aldrich Syndrome: a model for defective actin reorganization, cell trafficking and synapse formation. Curr Opin Immunol 2003; 15: 585–91
  • Pasic S., Micic D., Kuzmanovic M. Epstein‐Barr virus‐associated haemophagocytic lymphohistiocytosis in Wiskott‐Aldrich syndrome. Acta Paediatr 2003; 92: 859–61
  • Schmid I., Reiter K., Schuster F., Wintergerst U., Meilbeck R., Nicolai T., et al. Allogeneic bone marrow transplantation for active Epstein‐Barr virus‐related lymphoproliferative disease and hemophagocytic lymphohistiocytosis in an infant with severe combined immunodeficiency syndrome. Bone Marrow Transplant 2002; 29: 519–21
  • Grunebaum E., Zhang J., Dadi H., Roifman C. M. Haemophagocytic lymphohistiocytosis in X‐linked severe combined immunodeficiency. Br J Haematol 2000; 108: 834–7
  • Aleman K., Noordzij J. G., de Groot R., van Dongen J. J., Hartwig N. G. Reviewing Omenn syndrome. Eur J Pediatr 2001; 160: 718–25
  • Arico M., Bettinelli A., Maccario R., Clementi R., Bossi G., Danesino C. Hemophagocytic lymphohistiocytosis in a patient with deletion of 22q11.2. Am J Med Genet 1999; 87: 329–30
  • Touraine R. L., Pondarre C., Till M., Bertrand Y. Hemophagocytic lymphohistiocytosis and del22q11 [abstract]. Genetic Counseling 1999; 10: 114–5
  • Osugi Y., Hara J., Tagawa S., Takai K., Hosoi G., Matsuda Y., et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood 1997; 89: 4100–3
  • Schneider E. M., Lorenz I., Muller‐Rosenberger M., Steinbach G., Kron M., Janka‐Schaub G. E. Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer‐cell‐induced apoptosis. Blood 2002; 100: 2891–8
  • Takada H., Nomura A., Ohga S., Hara T. Interleukin‐18 in hemophagocytic lymphohistiocytosis. Leuk Lymphoma 2001; 42: 21–8
  • 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: 448–53
  • Takada H., Ohga S., Mizuno Y., Nomura A., Hara T. Increased IL‐16 levels in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 2004; 26: 567–73
  • Billiau A. D., Roskams T., Damme‐Lombaerts R., Matthys P., Wouters C. Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN‐gamma‐producing lymphocytes and IL‐6‐ and TNF‐alpha‐producing macrophages. Blood 2005; 105: 1648–51
  • Grossman W. J., Radhi M., Schauer D., Gerday E., Grose C., Goldman F. D. Development of hemophagocytic lymphohistiocytosis in triplets infected with HHV‐8. Blood 2005; 106: 1203–06
  • Grom A. A., Villanueva J., Lee S., Goldmuntz E. A., Passo M. H., Filipovich A. Natural killer cell dysfunction in patients with systemic‐onset juvenile rheumatoid arthritis and macrophage activation syndrome. J Pediatr 2003; 142: 292–6
  • Wulffraat N. M., Rijkers G. T., Elst E., Brooimans R., Kuis W. Reduced perforin expression in systemic juvenile idiopathic arthritis is restored by autologous stem‐cell transplantation. Rheumatology (Oxford) 2003; 42: 375–9
  • Kagi D., Ledermann B., Burki K., Seiler P., Odermatt B., Olsen K. J., et al. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin‐deficient mice. Nature 1994; 369: 31–7
  • Walsh C. M., Matloubian M., Liu C. C., Ueda R., Kurahara C. G., Christensen J. L., et al. Immune function in mice lacking the perforin gene. Proc Natl Acad Sci U S A 1994; 91: 10854–8
  • Mullbacher A., Hla R. T., Museteanu C., Simon M. M. Perforin is essential for control of ectromelia virus but not related poxviruses in mice. J Virol 1999; 73: 1665–7
  • Ghiasi H., Cai S., Perng G., Nesburn A. B., Wechsler S. L. Perforin pathway is essential for protection of mice against lethal ocular HSV‐1 challenge but not corneal scarring. Virus Res 1999; 65: 97–101
  • Rossi C. P., McAllister A., Tanguy M., Kagi D., Brahic M. Theiler's virus infection of perforin‐deficient mice. J Virol 1998; 72: 4515–9
  • Kagi D., Ledermann B., Burki K., Hengartner H., Zinkernagel R. M. CD8+ T cell‐mediated protection against an intracellular bacterium by perforin‐dependent cytotoxicity. Eur J Immunol 1994; 24: 3068–72
  • Denkers E. Y., Yap G., Scharton‐Kersten T., Charest H., Butcher B. A., Caspar P., et al. Perforin‐mediated cytolysis plays a limited role in host resistance to Toxoplasma gondii. J Immunol 1997; 159: 1903–8
  • Zhou P., Freidag B. L., Caldwell C. C., Seder R. A. Perforin is required for primary immunity to Histoplasma capsulatum. J Immunol 2001; 166: 1968–74
  • Jordan M. B., 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: 735–43
  • Matloubian M., Suresh M., Glass A., Galvan M., Chow K., Whitmire J. K., et al. A role for perforin in downregulating T‐cell responses during chronic viral infection. J Virol 1999; 73: 2527–36
  • Badovinac V. P., Hamilton S. E., Harty J. T. Viral infection results in massive CD8+ T cell expansion and mortality in vaccinated perforin‐deficient mice. Immunity 2003; 18: 463–74
  • Kagi D., Odermatt B., Mak T. W. Homeostatic regulation of CD8+ T cells by perforin. Eur J Immunol 1999; 29: 3262–72
  • Peng S. L., Moslehi J., Robert M. E., Craft J. Perforin protects against autoimmunity in lupus‐prone mice. J Immunol 1998; 160: 652–60
  • Spielman J., Lee R. K., Podack E. R. Perforin/Fas‐ligand double deficiency is associated with macrophage expansion and severe pancreatitis. J Immunol 1998; 161: 7063–70
  • Malipiero U., Frei K., Spanaus K. S., Agresti C., Lassmann H., Hahne M., et al. Myelin oligodendrocyte glycoprotein‐induced autoimmune encephalomyelitis is chronic/relapsing in perforin knockout mice, but monophasic in Fas‐ and Fas ligand‐deficient lpr and gld mice. Eur J Immunol 1997; 27: 3151–60
  • Liu B., Mori I., Hossain M. J., Dong L., Chen Z., Kimura Y. Local immune responses to influenza virus infection in mice with a targeted disruption of perforin gene. Microb Pathog 2003; 34: 161–7
  • Kemper C., Chan A. C., Green J. M., Brett K. A., Murphy K. M., Atkinson J. P. Activation of human CD4+ cells with CD3 and CD46 induces a T‐regulatory cell 1 phenotype. Nature 2003; 421: 388–92
  • Grossman W. J., Verbsky J. W., Barchet W., Colonna M., Atkinson J. P., Ley T. J. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004; 21: 589–601
  • Grossman W. J., Verbsky J. W., Tollefson B. L., Kemper C., Atkinson J. P., Ley T. J. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 2004; 104: 2840–8
  • Grossman W. J., Verbsky J. W., Yang L., Berg L. J., Fields L. E., Chaplin D. D., et al. Dysregulated myelopoiesis in mice lacking Jak3. Blood 1999; 94: 932–9
  • Henter J. I., Elinder G., Finkel Y., Soder O. Successful induction with chemotherapy including teniposide in familial erythrophagocytic lymphohistiocytosis. Lancet 1986; 2: 1402
  • Fisher A., Virelizier J. L., Arenzana F., Perez A., Nezelof C., Griscelli C. Treatment of four patients with erythrophagocytic lymphohistiocytosis by a combination of epipodophyllotoxin, steroids, intrathecal methotrexate and cranial irradiation. Pediatrics 1985; 76: 263–8
  • Bolme P., Henter J. I., Winiarski J., Elinder G., Ljungman P., Lonnerholm G., et al. Allogeneic bone marrow transplantation for hemophagocytic lymphohistiocytosis in Sweden. Bone Marrow Transplant 1995; 15: 331–5
  • Baker K. S., DeLaat C. A., Steinbuch M., Gross T. G., Shapiro R. S., Loechelt B., et al. Successful correction of hemophagocytic lymphohistiocytosis with related or unrelated bone marrow transplantation. Blood 1997; 89: 3857–63
  • Henter J. I., Samuelsson‐Horne A., Arico M., Egeler R. M., Elinder G., Filipovich A. H., et al. Treatment of hemophagocytic lymphohistiocytosis with HLH‐94 immunochemotherapy and bone marrow transplantation. Blood 2002; 100: 2367–73
  • Ishii E., Ohga S., Aoki T., Yamada S., Sako M., Tasaka H., et al. Prognosis of children with virus‐associated hemophagocytic syndrome and malignant histiocytosis: correlation with levels of serum interleukin‐1 and tumor necrosis factor. Acta Haematol 1991; 85: 93–9
  • Imashuku S., Hibi S., Fujiwara F., Ikushima S., Todo S. Haemophagocytic lymphohistiocytosis, interferon‐gamma‐naemia and Epstein‐Barr virus involvement. Br J Haematol 1994; 88: 656–8
  • Henter J. I., Elinder G., Soder O., Hansson M., Andersson B., Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 1991; 78: 2918–22
  • Verbsky J. W., White A. J. Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. J Rheumatol 2004; 31: 2071–5
  • Fisman D. N. Hemophagocytic syndromes and infection. Emerg Infect Dis 2000; 6: 601–8

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