Comprehensive analyses and characterization of haemophagocytic lymphohistiocytosis in vietnamese children

research paper Comprehensive analyses and characterization of haemophagocytic lymphohistiocytosis in Vietnamese children Lam T My,1,2 Le B Lien,1 Wen-Chuan Hsieh,3 Toshihiko Imamura,4 Tran N K Anh,1 Phan N L Anh,1 Nguyen T Hung,1 Fan-Chen Tseng,3 Chia-Yu Chi,3 Ngo T H Dao,5 Duong T M Le,5 Le Q Thinh,5 Tran T Tung,5 Shinsaku Imashuku,4 Tang C Thuong1 and Ih-Jen Su3,6 Department of Clinical Haematology, Children Hospital No 1, 2Department of Paediatrics, The University of Medicine and Pharmacy, Ho-ChiMinh City, Vietnam, 3Division of Infectious Diseases, National Health Research Institutes, Tainan, Taiwan, 4Department of Haematology, Kyoto Prefecture University of Medicine, Kyoto, Japan, 5Department of Laboratory Haematology, Children’s Hospital No 1, Ho-Chi-Minh City, Vietnam, and 6Department of Pathology, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan Received 13 July 2009; accepted for publication September 2009 Correspondence: Dr Ih-Jen Su, Division of Infectious Diseases, National Health Research Summary Haemophagocytic lymphohistiocytosis (HLH) is a fatal haematological disorder with diverse aetiology This prospective study was undertaken to characterize HLH cases in Vietnamese children Clinical and laboratory data, genetic analyses and outcome of the HLH patients were analysed A total of 33 patients were enrolled from March 2007 to December 2008, with a median age of years Mutations of the SH2D1A (SAP) and PRF1 genes were detected in one patient, respectively The virus association was high, up to 63Ỉ6% (21/33), including Epstein–Barr virus (19/33), cytomegalovirus (2/33) and dengue virus (2/33) Five patients had malignant lymphoma and two had autoimmune diseases Twenty-eight patients were treated according to the HLH-2004 protocol The first response rate was 64Ỉ3% (18/28), with an early death rate of 35Ỉ7% (10/28) High levels of interferon-c, interleukin-10, MIG and interferon-inducible protein-10 (IP-10) were associated with early mortality (P < 0Ỉ05) Reactivation among the responders was high (9/18) and the uneventful resolution was low (3/18) after a median follow-up of 35 weeks In conclusion, the majority of HLH cases are associated with virus infections in Vietnamese children Familial HLH is rare The frequent reactivation and high mortality demands a more appropriate therapeutic regimen in tropical areas like Vietnam Keywords: haemophagocytic lymphohistiocytosis, Epstein–Barr virus, SAP, cytokine storm, Vietnam Institutes, 367 Sheng-Li Road, Tainan, Taiwan E-mail: suihjen@nhri.org.tw Haemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal haematological disorder frequently associated with severe infections and malignancies (Mathew et al, 2000; Henter et al, 2002; Gupta et al, 2009) The disease is characterized by prolonged fever, jaundice, hepatosplenomegaly, pancytopenia and coagulopathy (Henter et al, 2002) In past decades, a series of studies have revealed that HLH results from the deregulation of natural killer cells and cytotoxic T cell response, leading to systemic proinflammatory cytokine injuries and macrophage activation with haemophagocytosis in bone marrow and the lymphoid system (Ueda et al, 2006; Henter et al, 2007) Current advances in molecular studies have further documented that a substantial percentage of HLH patients are primarily associated with mutations of the SH2D1A (SAP), PRF1, or UNC13D genes (Ohno et al, 2003; Henter et al, 2007; Su, 2008) Furthermore, HLH may accompany autoimmune disorders and malignancies, such as lymphomas (Gutierrez et al, 2003; Krenova et al, 2007) Therefore, HLH encompasses a diverse spectrum of diseases and their distribution may vary among different ethnic populations or geographic regions Recently, a therapeutic protocol of HLH-2004 by the Histiocyte Society has been widely adopted with specific treatments based on disease severity and particular genetic abnormalities (Imashuku et al, 2000; Henter et al, 2007; Horne et al, 2008; Su, 2008; Yamada et al, 2008) Haemophagocytic lymphohistiocytosis is not well documented in Vietnamese children Before 2000, the recognition of this disease was hampered by the lack of appropriate guidelines for diagnosis Based on the guidelines for HLH-94 and HLH-2004 (Henter et al, 2002, 2007), HLH was increasingly diagnosed and treated at the Children’s Hospital No of Ho-Chi-Minh City (HCMC), Vietnam The general outcome, ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 148, 301–310 First published online 27 October 2009 doi:10.1111/j.1365-2141.2009.07957.x L T My et al however, was poor The major challenge for the paediatricians was, and continues to be, the diagnostic criteria and differential diagnosis of HLH, particularly in a tropical region where dengue and other infectious diseases prevail (Mathew et al, 2000; Gurgey et al, 2005) In order to understand the potential diagnostic and therapeutic problems and to characterize the distribution of disease entities of HLH in Vietnam, a prospective study on the diagnosis and treatment of HLH was launched by collaboration between Children’s Hospital No.1, HCMC, Vietnam and the Division of Infectious Diseases of the National Health Research Institutes, Taiwan, with consultation from Professor Shinsaku Imashuku, Kyoto, Japan Through this collaborative study, the clinical assessments, cytokine profiles, virological etiologies, family studies and genetic analyses and treatment outcome of HLH in Vietnamese children were analysed taken at diagnosis The diagnosis of systemic lupus erythematosus (SLE) or other autoimmune diseases was based on the criteria from the American Rheumatism Association (Tan et al, 1982) Patients with malignancy-associated HLH were transferred to the National Cancer Hospital or the Hospital of Blood and Transfusion of HCMC for further treatment Patients with immune disorder-associated HLH, including SLE or juvenile idiopathic arthritis (JIA), at first were treated according to the guidelines of HLH-2004 with ciclosporin and dexamethasone But after enough criteria for the positive diagnosis of SLE or JIA were reached, they were further treated pursuant to the guidelines for SLE or JIA Patients with infectious diseases-associated HLH, such as bacterial (e.g typhoid fever, tuberculosis) or parasitic (malaria), were treated with specific antibiotics or anti-malarial drugs according to the guidelines of the Ministry of Public Health, Vietnam Materials and methods Cytokine and chemokine studies Patients and diagnosis A prospective study on HLH was carried out from March 2007 to 30 December 2008 at the Children’s Hospital No.1, HCMC, Vietnam The criteria for diagnosis of HLH were based on the guideline of the HLH-2004 proposed by the Haemophagocytic Lymphohistiocytosis Study Group (Henter et al, 2007), and patients who fulfilled at least five of the following signs or laboratory parameters were enrolled: fever (higher than 38°C for more than d), splenomegaly or hepatomegaly, cytopenia (affecting ‡2 of three lineages in the peripheral blood: haemoglobin (