Hemophagocityc Lymphohistiocytosis: A Spectrum from the Genetic Disorder to the Macrophage Activation Syndrome
DOI:
https://doi.org/10.51481/amc.v53i2.728Keywords:
hemophagocytic lymphohistiocytosis, hemophagocytic syndrome, macrophage activation syndrome, juvenile-onset systemic lupus erythematosus, systemic juvenile idiopathic arthritis, Epstein-Barr virus, ferritin, hemophagocytosis, bone marrow transplantationAbstract
Hemophagocytic lymphohistiocytosis is characterized by a severe hyperinflammatory condition, with macrophages and T cells activation and expansion, without regulatory pathways for the termination of the infl ammatory activity. Hemophagocytic syndromes are clinical translation of an overwhelmed infl ammatory response. The term hemophagocytic lymphohistiocytosis applies to all the variants of the syndrome and macrophage activation syndrome refers to the variant associated with autoimmune diseases. Primary cases are related to a familiar autosomic recessive disease and the secondary ones to primary immunodefi ciencies, infection, malignancy and autoimmune diseases. Physiopathology of the disease is related mainly to the aggressive macrophage and histiocyte proliferation and phagocytosis of blood cells. An impaired function of NK cells and cytotoxic T-cells, increase cell activation and expansion and cytokine production inducing macrophage activation, tissue infi ltration and tissue damage. The main symptoms are prolonged fever, cytopenias, hepatosplenomegaly, and hemophagocytosis. Biochemical markers include elevated ferritin and triglycerides and low fi brinogen. Bone marrow hemophagocytosis is present in more than 80% of the cases at diagnosis. Treatment targets activated T-cells an histiocytes, combining chemotherapy, immunosuppressors and in selected cases hematopoyetic stem cell transplantation. Treatment produced a positive change in patient survival. HLH-2004 treatment protocol is an standarized guideline that combine etoposide, dexamethasone and cyclosporine A. In Costa Rica 60 cases have been reported in children, with a 44% mortality.
Downloads
References
Filipovich AH. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders. Immunol Allergy Clin N Am 2008; 28: 293-313.
Henter JI, Arico M, Elinder G, Imashuku S, Janka G. Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998; 12: 417433.
Scott R, Robb-Smith A. Histiocytic medullary reticulosis. Lancet 1939; 2: 194-198.
Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child 1952; 27: 519-525.
Janka G. Hemophagocytic lymphohistiocytosis: when the immune system runs amok. Klin Padiatr 2009; 221: 278-285.
Arceci RJ. The histiocytoses: the fall of the tower of Babel. Eur J Cancer 1999; 35: 747-769.
Tristano AG. Macrophage activation syndrome: a frequent but underdiagnosed complication associated with rheumatica diseases. Med Sci Monit 2008; 14: 27-36.
Bhattacharyya M, Ghosh MK. Hemophagocytic lymphohistiocytosis - Recent concept. J Assoc Physicians India 2008; 56: 453-457.
Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007; 166: 95-109.
Créput C, Galicier L, Buyse S, Azoulay E. Understanding organ dysfunction in hemophagocytic lymphohistiocytosis. Intensive Care Med 2008; 34: 1177-1187.
Stinchcombe J, Bossi G, Griffi ths G. Linking albinism and immunity: the secrets of secretory lysosomes. Science 2004; 305: 55-59.
Grom AA, Mellins ED. Macrophage activation syndrome: advances towards understanding pathogenesis. Curr Opin Rheumatol 2010; 22: 561-566.
Menasche G, Feldmann J, Fischer A, Basile Gde S. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev 2005; 203: 165-179.
Egeler RM, Shapiro R, Loechelt B, Filipovich A. Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 1996; 18: 340-345.
Janka GE. Hemophagocytic syndromes. Blood Rev 2007; 21: 245-253.
Henter JI, Elinder G. Cerebromeningeal haemophagocytic lymphohistiocytosis. Lancet 1992; 339: 104-109.
Howells DW, Strobel S, Smith I, Levinsky RJ, Hyland K. Central nervous system involvement in the erythrophagocytic disorders of infancy: the role of cerebroespinal fl uid neopterins in their differential diagnosis and clinical management. Pediatr Res 1990; 28: 116-119.
Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008; 50: 1227-1235.
Lin T, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer 2011; 56: 154-155
Henter JI, Horne AC, Aricó M, Egeler RM, Filipovich A, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.
Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr 2005; 146: 598-604.
Daví S, Consolaro A, Guseinova D, Pistorio A, Ruperto N, Martini A, et al. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol 2011; 38: 1-5.
Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paeditr Scand 1991; 80: 428-435.
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: 197-203.
Allen M, De Fusco C, Legrand F, Clementi R, Conter V, Danesino C, et al. Familial hemophagocytic lymphohistiocytosis: how late can onset be? Haematologica 2001; 86: 499-503.
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: 2266-2267.
Trottestam H, Beutel K, Meeths M, Carlsen N, Heilmann C, PaÅ¡ić S, et al. Treatment of the X-linked lymphoproliferative, Griscelli and Chédiak-Higashi syndromes by HLH directed therapy. Pediatr Blood Cancer 2009; 52: 268-272.
Bejaoui M, Veber F, Girault D, Gaud C, Blanche S, Griscelli C, et al. The accelerated phase of Chediak-Higashi syndrome. Arch Fr Pediatr 1989; 46: 733-736.
Ortuño FJ, Fuster JL, Jerez A. Síndrome de Chediak-Higashi. Med Clin (Barc) 2010; 135: 512-518.
Van Gele M, Dynoodt P, Lambert J. Griscelli syndrome: a model system to study vesicular traffi cking. Pigment Cell Melanoma Res 2009; 22: 268-282.
Rezaei N, Mahmoudi E, Aghamohammadi A, Das R, Nichols KE. X-linked lymphoproliferative syndrome: a genetic condition typifi ed by the triad of infection, immunodefi ciency and lymphoma. Br J Haematol 2011; 152: 13-30.
Machaczka M, Vaktnás J, Klimkowska M, Hágglund H. Malignancyassociated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center. Leuk Lymphoma 2011: en prensa.
Imashuku S. Treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH); update 2010. J Pediatr Hematol Oncol 2011; 33: 35-39.
Özdemir H, Çiftçi E, Ünal ?nce E, Ertem M, ?nce E, Do?ru Ü. Hemophagocytic lymphohistiocytosis associated with 2009 pandemic Infl uenza A (H1N1) virus infection. J Pediatr Hematol Oncol 2011; (en prensa).
Hanson D, Walter AW, Powell J. Ehrlichia-induced hemophagocytic lymphohistiocytosis in two children. Pediatr Blood Cancer 2011; 56:661-663.
Dhote R, Simon J, Papo T, Detournay B, Sailler L, Andre MH, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 2003; 49: 633-639.
Parodi A, Daví S, Pringe A, Pistoro 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: 3388-3399.
Pringe A, Trail L, Ruperto N, Buoncompagni A, Loy A, Breda L, et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus: an under-recognized condition? Lupus 2007; 16: 587592.
Singh S, Chandakasan S, Ahluwalia J, Suri D, Rawat A, Ahmed N, et al. Macrophage activation syndrome in children with systemic onset juvenile idiopathic arthritis: clinical experience from northwest India. Rheumatol Int 2011; (en prensa)
Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM. Ferritin for the clinician. Blood Rev 2009; 23: 95-104.
Henter JI, Aricó M, Egeler RM, Elinder G, Favara BE, Filipovich AH, et al. HLH-94: a treatment protocol for hemophatocytic lymphohistiocytosis. Med Pediatr Oncol 1997; 28: 342-347
Lee JS, Kang JH, Lee GK, Park HJ. Successful treatment of EpsteinBarr virus-associated hemophagocytic lymphohistiocytosis with HLH-94 protocol. J Korean Med Sci 2005; 20: 209-214.
Ishii E, Ohga S, Imashuku S, Kimura N, Ueda I, Morimoto A, et al. Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on japanese experiences. Crit Rev Oncol Hematol 2005; 53: 209-223.
Horne A, Janka G, Maarten ER, Gadner H, Imashuku S, Ladisch S, et al. Haematopoietic stem cell transplantation in haemophagocytic limphohistiocytosis. Br J Haematol 2005; 129: 622-630
Ouachee-Chardin M, Elie C, de Saint Basile G, Le Deist F, Mahlaoui N, Picard C, et al. Hematopietic stem cell transplantation in hemophagocytic lymphohistiocytosis: a single-center report of 48 patients. Pediatrics 2006; 117: 743-750.
Cooper N, Rao K, Gilmour K, Hadad L, Adams S, Cale C, et al. Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis. Blood 2006; 107: 1233-1236.
Yoon HS, Im HJ, Moon HN, Lee JH, Kim HJ, Yoo KH, et al. The outcome of hematopoietic stem cell transplantation in Korean children with hemophagocytic lymphohistiocytosis. Pediatr Transplant 2010; 14: 735-740.
Strout MP, Seropian S, Berliner N. Alemtuzumab as a bridge to allogeneic SCT in atypical hemophagocytic limphohistiocytosis. Nat Rev Clin Oncol 2010; 7: 415-420.
Bruck N, Suttorp M, Kabus M, Heubner G, Gahr M, Pessler F. Rapid and sustained remission of systemic juvenile idiopathic arthritisassociated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol 2011; 17: 23-27.
Castillo-Salas S. Síndrome de activación macrofágica en niños. Tesis para licenciatura. UNIBE: San José, pp: 1-97, 2000.
Downloads
Published
Issue
Section
License
Copyright (c) 2011 Acta Médica Costarricense
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Los autores que publican en la revista Acta Médica Costarricense pueden distribuir, copiar, remezclar, retocar, leer, descargar, imprimir, buscar y crear a partir de su obra de modo no comercial, indicando los créditos a la revista y sus autores y compartir su obra en las mismas condiciones. Para ello se aplica la licencia Creative Commons Reconocimiento-NoComercial-CompartirIgual 4.0 Internacional(CC BY-NC-SA 4.0)
