血球貪食症候群 Hemophagocytic lymphohistiocytosis   
はじめに
血球貪食性リンパ組織球症 は常染色体劣性の家族性リンパ組織球症や家族性 エリスロ貪食赤組織球症 VAHS などの名前で知られている。

これらは致命的となり得る疾患で新生児から18才までの年齢に最も多いが、より高齢者でも報告はある。
primary HLHは先天性、secondary HLH は、viral illness, autoimmune disease, lymphomaなどに引き続いておこる。
頻度
△スェーデンで1間に100万人に1−2名 5万人の誕生に1名
男女比1:1 解剖前に診断がついたのが11-32%という報告がある(それほど診断が難しい)
○ Fever — 91 percent
○ Hepatomegaly — 90 percent
○ Splenomegaly — 84 percent
○ Neurologic symptoms — 47 percent
○ Rash — 43 percent
○ Lymphadenopathy — 42 percent

∵原因となるウィルス
Epstein-Barr virus, cytomegalovirus, parvovirus, herpes simplex, varicella-zoster, measles [9], as well as human herpes virus-8 and HIV infection, alone or in combination


1.Chen TL, Wong WW, Chiou TJ. Hemophagocytic syndrome: an unusual manifestation of acute human immunodeficiency virus infection. Int J Hematol 2003; 78:450.


2.Fardet L, Blum L, Kerob D, et al. Human herpesvirus 8-associated hemophagocytic lymphohistiocytosis in human immunodeficiency virus-infected patients. Clin Infect Dis 2003; 37:285.


3.Grossman WJ, Radhi M, Schauer D, et al. Development of hemophagocytic lymphohistiocytosis in triplets infected with HHV-8. Blood 2005; 106:1203.


4.Huang DB, Wu JJ, Hamill RJ. Reactive hemophagocytosis associated with the initiation of highly active antiretroviral therapy (HAART) in a patient with AIDS. Scand J Infect Dis 2004; 36:516.


5.Risdall RJ, Brunning RD, Hernandez JI, Gordon DH. Bacteria-associated hemophagocytic syndrome. Cancer 1984; 54:2968.

∵ウィルス以外の原因
SLE rheumatoid arthritis, Still's disease, polyarteritis nodosa, mixed connective tissue disease, pulmonary sarcoidosis, systemic sclerosis, and Sjogren's syndrome

1.Wong KF, Hui PK, Chan JK, et al. The acute lupus hemophagocytic syndrome. Ann Intern Med 1991; 114:387.


2.Morris JA, Adamson AR, Holt PJ, Davson J. Still's disease and the virus-associated haemophagocytic syndrome. Ann Rheum Dis 1985; 44:349.


3.Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 2003; 49:633.

∵薬剤性 
 Drug-induced hypersensitivity syndrome also called drug rash with eosinophilia and systemic symptoms (DRESS)
Ben m'rad M, Leclerc-Mercier S, Blanche P, et al. Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients. Medicine (Baltimore) 2009; 88:131.
∵白血病
HLH is also found coincident with leukemias and lymphomas

1.Falini B, Pileri S, De Solas I, et al. Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood 1990; 75:434.


2.Okuda T, Sakamoto S, Deguchi T, et al. Hemophagocytic syndrome associated with aggressive natural killer cell leukemia. Am J Hematol 1991; 38:321.


3.Miyahara M, Sano M, Shibata K, et al. B-cell lymphoma-associated hemophagocytic syndrome: clinicopathological characteristics. Ann Hematol 2000; 79:378.


4.Shimazaki C, Inaba T, Nakagawa M. B-cell lymphoma-associated hemophagocytic syndrome. Leuk Lymphoma 2000; 38:121.


5.Pastore RD, Chadburn A, Kripas C, Schattner EJ. Novel association of haemophagocytic syndrome with Kaposi's sarcoma-associated herpesvirus-related primary effusion lymphoma. Br J Haematol 2000; 111:1112.


6.Ménard F, Besson C, Rincé P, et al. Hodgkin lymphoma-associated hemophagocytic syndrome: a disorder strongly correlated with Epstein-Barr virus. Clin Infect Dis 2008; 47:531.


7.O'Brien MM, Lee-Kim Y, George TI, et al. Precursor B-cell acute lymphoblastic leukemia presenting with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008; 50:381.

それ以外の原因
∵ Cytophagic histiocytic panniculitis, a rare systemic disorder consisting of lobular panniculitis, fever, hepatosplenomegaly, liver failure, infiltration with cytophagic histiocytes, and an association with subcutaneous panniculitis-like T-cell lymphoma, may also have features of secondary HLH


∵ after the use of umbilical cord blood for hematopoietic cell transplantation in adults
Takagi S, Masuoka K, Uchida N, et al. High incidence of haemophagocytic syndrome following umbilical cord blood transplantation for adults. Br J Haematol 2009; 147:543.


∵ As many as 25 percent of all HLH cases are familial and frequently associated with parental consanguinity.(血縁)
△大人のHLHの疫学は不明であるが薬剤などで免疫不全状態時の感染に多いようである。


#鑑別疾患


#fibrile illness
# Liver and coagulopathy
# Multiple organ failure syndrome
# Child abuse
# Encephalitis

○病理所見
○ aggressive proliferation of normal histiocytes and T-lymphocytes in various tissues.
 Hemophagocytosis of red cells (erythrophagocytosis), other white blood cells, or platelets in the bone marrow
○ spleen, or lymph nodes is the key diagnostic finding
○Bone marrow from a child with hemophagocytic syndrome
○ The macrophages in HLH do not have the cellular atypia associated with malignant histiocytes
○Results from the HLH-94 study indicated that a ferritin level >500 microg/L was 80 percent specific for the diagnosis of HLH.
○Specialized tests that may be helpful in supporting the diagnosis of HLH include histologic evidence of chronic persistent hepatitis, low perforin expression and low natural killer cell activity


Kogawa K, Lee SM, Villanueva J, et al. Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members. Blood 2002; 99:61.