II. Epidemiology

  1. Rare

III. Pathophysiology

  1. Impaired Natural Killer Cell activity triggers over-activation of Macrophages and cytotoxic T Cells (CD8 T Cells)
  2. Immune System overactivation with histiocyte, T-Cell and Macrophage accumulation in the skin, liver and Spleen
  3. Results in Phagocytosis of Red Blood Cells, White Blood Cells and Platelets
  4. Also results in increased Cytokine release with a severe inflammatory response

IV. Causes

  1. Primary (Hereditary)
    1. Diagnosed in infancy
  2. Secondary (Significant physiologic stressors)
    1. Infection
    2. Immunodeficiency
    3. Autoimmune Conditions
    4. Malignancy

VI. Findings

  1. Fever (>90%)
  2. Splenomegaly (>80%)
  3. Hepatomegaly (>60%)
  4. Respiratory dysfunction (>30%)
  5. CNS dysfunction (>30%)

VII. Labs

  1. Labs should also address differential diagnosis (e.g. Sepsis)
  2. Complete Blood Count
    1. Pancytopenia
  3. Comprehensive Metabolic Panel
    1. Abnormal Liver Function Tests
    2. Hypoalbuminemia
  4. Serum Ferritin
    1. Levels are frequently >2000 mcg/L
  5. Coagulation Studies (e.g. PTT, INR)
    1. Coagulopathy
    2. Fibrinogen decreased
    3. D-Dimer increased
  6. Other Studies
    1. Serum Triglycerides increased

VIII. Management

  1. Patients typically present with toxic appearance
    1. ABC Management
    2. Fluid Resuscitation
    3. Antibiotics are typically started (due to risk of underlying infectious cause)
  2. Consult Hematology and Intensive Care Medicine
    1. Discuss evaluation and management
    2. Antiiflammatory agents are typically used
      1. Corticosteroids
      2. Biologic agents (e.g. Anakinra, Ruxolitinib, etoposide)

IX. Prognosis

  1. Mortality 20 to 80% (increased with delayed diagnosis)

X. Resources

  1. Konkol S, Rai M (2022) Lymphohistiocytosis, StatPearls, Treasure Island, FL,
    1. https://www.ncbi.nlm.nih.gov/books/NBK557776/

XI. References

  1. Long and Lentz in Swadron (2022) EM: Rap 22(8): 11-2

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Related Studies

Ontology: Lymphohistiocytosis, Hemophagocytic (C0024291)

Definition (NCI_NCI-GLOSS) A rare disorder in which histiocytes and lymphocytes (types of white blood cells) build up in organs including the skin, spleen, and liver, and destroy other blood cells. Hemophagocytic lymphohistiocytosis may be inherited or caused by certain conditions or diseases, including infections, immunodeficiency (inability of the body to fight infections), and cancer.
Definition (NCI) A rare but potentially life-threatening disorder characterized by the proliferation of histiocytes and macrophages and phagocytosis of red blood cells, white blood cells, and platelets. It may be inherited or secondary, due to infections, autoimmune disorders, or underlying malignancies. Signs and symptoms include fever, lymphadenopathy, hepatomegaly, splenomegaly, and pancytopenia.
Definition (NCI) A classification of rare, non-neoplastic, proliferative disorders of the hematologic system. Primary or familial hemophagocytic lymphohistiocytosis (HLH) is inherited with an autosomal recessive pattern with five known subtypes differentiated by specific genetic mutations. Secondary manifestation of HLH is usually seen in hyperactivated immunologic states such as infection, autoimmune disease or malignancy. Histiocytes in the bone marrow, spleen or lymph nodes become activated to the point that phagocytosis proceeds unchecked. Clinical signs usually present within the first decade and include fever, jaundice, hepatosplenomegaly, lymphadenopathy and skin rash. Prompt initiation of treatment improves survival though prognosis remains poor even with intervention.
Definition (MSH) A group of related disorders characterized by LYMPHOCYTOSIS; HISTIOCYTOSIS; and hemophagocytosis. The two major forms are familial and reactive.
Concepts Disease or Syndrome (T047)
MSH D051359 , D015616
ICD9 288.4
ICD10 D76.1
SnomedCT 190958003, 234437005, 127069007
English Haemophagocyt lymphohistiocyto, Hemophagocytic syndromes, hemophagocytic lymphohistiocytosis, hemophagocytic syndrome, hemophagocytic syndrome (diagnosis), Lymphohistiocytosis, Hemophagocytic [Disease/Finding], haemophagocytic syndrome, hemophagocytic syndromes, haemophagocytic syndromes, Hemophagocytic Disorder, Hemophagocytic Syndrome, Haemophagocytic lymphohistiocytosis (disorder), hemophagocytic lymphohistiocytosis (diagnosis), HLH, Haemophagocytic lymphohistiocytosis, Haemophagocytic syndrome, Hemophagocytic syndrome, Hemophagocytic lymphohistiocytosis (disorder), Hemophagocytic lymphohistiocytosis, Hemophagocytic syndrome (disorder), hemophagocytic; syndrome, lymphohistiocytosis; hemophagocytic, syndrome; hemophagocytic, Hemophagocytic Lymphohistiocytosis, Hemophagocytic Lymphohistiocytoses, Lymphohistiocytoses, Hemophagocytic, Lymphohistiocytosis, Hemophagocytic, Hemophagocytic Syndromes
Dutch hemofagocytair syndroom, hemofagocytaire lymfohistiocytose, hemofagocytair; syndroom, lymfohistiocytose; hemofagocytair, syndroom; hemofagocytair, Hemofagocytaire lymfohistiocytose, Lymfohistiocytose, hemofagocytaire
German haemophagozytisches Syndrom, Haemophagozytaere Lymphohistiozytose, Haemophagozytische Lymphohistiozytose, Hämophagozytäre Syndrome, Lymphohistiozytose, hämophagozytäre
Italian Sindrome emofagocitica, Sindromi emofagocitiche, Linfoistiocitosi emofagocitica
Portuguese Síndroma hemofagocítico, Síndrome hemofagocítico, Linfohistiocitose hemofagocítica, Linfohistiocitose Hemofagocítica, Síndromes Hemafagocíticas
Spanish Síndrome hemofagocítico, Linfohistiocitosis hemofagocítica, linfohistiocitosis hemofagocítica (trastorno), linfohistiocitosis hemofagocítica, síndrome hemofagocítico (trastorno), síndrome hemofagocítico, Linfohistiocitosis Hemofagocítica, Síndromes Hemofagocíticos
Japanese ケッキュウドンショクショウコウグン, 感染症合併血球貪食症候群, 血球貪食症候群-感染症合併, 家族性血球貪食性リンパ組織球症, 感染症関連血球貪食症候群, 血球貪食性リンパ組織球症-家族性, リンパ組織球増多症-血球貪食, 血球貪食リンパ組織球増多症, 血球貪食症候群-感染症関連, リンパ組織球症-血球貪食性, 血球貪食症候群, 血球貪食症候群-ウイルス関連, 血球貪食性リンパ組織球症, ウイルス関連血球貪食症候群, ケッキュウドンショクセイリンパソシキキュウショウ
Czech lymfohistiocytóza hemofagocytární, hemofagocytární syndromy, lymfohistiocytóza hemofagocytující, Syndrom hemofagické histiocytózy, Hemofagocytový syndrom, Hemofagocytující lymfohistiocytóza, hemofagocytární lymfohistiocytóza
Finnish Hemofagosyyttinen lymfohistiosytoosi
Russian GEMOFAGOTSITARNYI SINDROM, INFEKTSIIA-ASSOTSIIROVANNYI, REAKTIVNYI GEMOFAGOTSITARNYI SINDROM, GEMOFAGOTSITARNYE SINDROMY, GEMOFAGOTSITARNYI LIMFOGISTIOTSITOZ SEMEINYI, SEMEINYI GEMOFAGOTSITARNYI LIMFOTSITOZ, LIMFOGISTIOTSITOZ GEMOFAGOTSITARNYI, GEMOFAGOTSITARNYI SINDROM REAKTIVNYI, ЛИМФОГИСТИОЦИТОЗ ГЕМОФАГОЦИТАРНЫЙ, ГЕМОФАГОЦИТАРНЫЕ СИНДРОМЫ, ГЕМОФАГОЦИТАРНЫЙ ЛИМФОГИСТИОЦИТОЗ СЕМЕЙНЫЙ, ГЕМОФАГОЦИТАРНЫЙ СИНДРОМ РЕАКТИВНЫЙ, ГЕМОФАГОЦИТАРНЫЙ СИНДРОМ, ИНФЕКЦИЯ-АССОЦИИРОВАННЫЙ, РЕАКТИВНЫЙ ГЕМОФАГОЦИТАРНЫЙ СИНДРОМ, СЕМЕЙНЫЙ ГЕМОФАГОЦИТАРНЫЙ ЛИМФОЦИТОЗ
Swedish Lymfohistiocytos, hemofagocyterande
Korean 혈구탐식성 림프조직구증
Polish Limfohistiocytoza hemofagocytarna, Limfohistiocytoza hemofagocytowa, Zespół hemofagocytarny
Hungarian Haemophagocytás syndroma, Haemophagocytás szindróma, Haemophagocytás lymphohistiocytosis, Hemophagocytikus lymphohistiocytosis
Norwegian Hemofagocyttær lymfohistiocytose, Hemofagocyttisk lymfohistiocytose
French LHH (LymphoHistiocytose Hémophagocytaire), Lymphohistiocytose hémophagocytaire, Syndrome hémophagocytaire, Syndromes hémophagocytaires