Hemophagocytic lymphohistiocytosis

Background

  • Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome 
  • HLH can be precipitated by many underlying conditions; it represents a highly stimulated but ineffective immune response and is classified as one of the cytokine storm syndromes
  • HLH can present in all age groups
  • HLH is caused by uncontrolled proliferation of activated lymphocytes and macrophages
  • All symptoms and signs of HLH may also be found to varying extents in the context of drastic immune activation (particularly in the setting of severe infectious disease) in individuals with a normal ability to control inflammatory response; HLH represents the loss of ability to control this response, either through genetic predisposition or due to an overwhelmingly potent immunological challenge

 

Etiologies

  • Genetic forms of HLH are due to defects in transport, processing, and function of cytotoxic granules in natural killer cells and cytotoxic T lymphocytes; genetic forms of HLH can present in childhood or adulthood
  • Familial HLH (FHL) is a rare disease with autosomal recessive inheritance; four genetic defects, all involved in cytotoxic granule exocytosis or function, have been implicated; this constellation of diseases is therefore closely related to Chédiak–Higashi syndrome (CHS) and Griscelli syndrome 2 (GS-2)
  • Infectious agents are the most frequent trigger for the development of HLH in general, but in infants and very young children HLH is predominantly due to immune defects with mutations in genes responsible for cytotoxic function of natural killer cells and cytotoxic T lymphocytes
  • Acquired forms of HLH can be sparked by infections, autoinflammatory/autoimmune diseases, malignancy, and acquired immune deficiency (including HIV/AIDS)
  • The most common infectious etiology is Epstein-Barr virus (EBV)

 

Pathophysiology

  • Symptoms of HLH reflect immune activation and hypercytokinemia
  • Fever is caused by interleukins and tumor necrosis factor (TNF)
  • Cytokines suppress hematopoiesis; hematopoiesis is further suppressed by high levels of ferritin
  • Activated macrophages produce increased levels of plasminogen activator, leading to hyperfibrinolysis
  • Organomegaly, neurological symptoms, and cholestatic hepatitis occur as a result of widespread infiltration by activated lymphocytes and histiocytes

 

Pathology

 

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Figure 1. Hemophagocytosis in the bone marrow of an 18 year-old woman with EBV-associated HLH (Fishman, 2000).  Bone marrow evaluation revealed a hypocellular marrow with active hemophagocytosis.  The macrophage poised at the center of the above image appears engorged with phagocytosed erythrocytes. Fishman DN. Hemophagocytic syndromes and infection. Emerging Infectious Diseases. 2000; 6(6): 601-608.

 

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Figure 2. Bone marrow aspirate from a patient with known CLL diagnosis.  Aspirate displayed above reveals background lymphocytosis, scattered myeloid elements at all stages of maturation, and a single macrophage framed in the lower center of the image, having phagocytosed four intermediate erythroid precursors (John Lazarchick, American Society of Hematology image bank, 2008).

 

Clinical presentation and diagnostics

  • Cardinal symptoms of HLH are prolonged fever, hepatosplenomegaly, and pancytopenia; patients with poorly controlled disease can progress to bone marrow aplasia
  • CNS symptoms include reduced level of consciousness, meningismus, cranial nerve palsies, and seizures
  • Cardinal laboratory values include increased ferritin, triglycerides, transaminases, bilirubin, lactate dehydrogenase, soluble interleukin-2 receptor α-chain, and decreased fibrinogen
  • The differential for HLH includes septicemia, Wolman’s disease, osteopetrosis, autoimmune lymphoproliferative syndrome, neonatal hemochromatosis, Gaucher disease, Combined Immunodeficiency (CID), and Common Variable Immune Deficiency (CVID)
  • The clinician should ask three questions of the potential case of HLH: (1) Are clinical and laboratory parameters compatible with the acute syndrome HLH?, (2) Is there an underlying triggering condition?, and (3) Is there a hereditary predisposition?
  • The disease is defined by a set of eight parameters, called the HLH-2004 criteria; 5/8 criteria are necessary for diagnosis:

 

Table 1. HLH-2004 diagnostic criteria (adapted from Jenka and Lehmberg, 2014)

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Therapeutics

  • Treatment of HLH aims at suppressing hypercytokinemia and eliminating activated and infected cells
  • Treatment includes immunomodulatory and immunosuppressive agents, cytostatics, T-cell and cytokine antibodies
  • A cure for genetic forms of HLH can only be achieved with hematopoietic stem cell transplantation
  • Acquired HLH is treated according to the HLH-1994/HLH-2004 protocol: etoposide and dexamethasone, followed by maintenance therapy with cyclosporine A and pulses of etoposide and dexamethasone for patients with hereditary disease and a bridge to transplant
  • Overall five year survival with the HLH-1994 protocol reached 54%; results from HLH-2004 protocol are still pending
  • Once patients with acquired disease have reached remission they usually do not require further treatment or maintenance therapy

 

Reading

Allen CE and McClain KL. Pathophysiology and epidemiology of Hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program. 2015; 1: 1777-82.

Behrens EM. Macrophage activation syndrome in rheumatic disease: what is the role of the antigen presenting cell? Autoimmun Rev. 2008; 7(4): 305-308.

Faitelson Y and Grunebaum E. Hemophagocytic lymphohistiocytosis and primary immune deficiency disorders. Clin Immunol. 2014; 155(1): 118-125.

Fishman DN. Hemophagocytic syndromes and infection. Emerging Infectious Diseases. 2000; 6(6): 601-608.

Janka GE. Familial and acquired Hemophagocytic lymphohistiocytosis. Annual Review of Medicine 2012; 63(1): 233-246.

Janka GE and Lehmberg K. Hemophagocytic syndromes—an update. Blood Reviews. 2014; 28(4): 135-42.

Lee HY, Huang YC, Lin TY, et al. Primary Epstein-Barr virus infection associated with Kikuchi’s disease and Hemophagocytic lymphohistiocytosis: a case report and review of the literature. J Microbiol Immunol Infect. 2010; 43(3): 253-257.

Lehmberg K. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. British Journal of Harmatology 2012; 160(3): 275-287.

Malinowska I, Machaczka M, Popko K, et al. Hemophagocytic syndrome in children and adults.  Arch Immunol Ther Exp (Warsz). 2014; 62(5): 385-394.

Risma K and Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr. 2012; 24(1): 9-15.

Seo JJ. Hematopoietic cell transplantation for Hemophagocytic lymphohistiocytosis: recent advances and controversies. Blood Res 2015; 50(3): 131-139.

Verbsky JW and Grossman WJ. Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment,