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Haemophagocytic Lymphohistiocytosis

What Is Haemophagocytic Lymphohistiocytosis?
Haemophagocytic lymphohistiocytosis (HLH) is a term used to describe a life-threatening hyper-inflammatory syndrome. HLH is characterized by persistent fevers, rash, hepatosplenomegaly, cytopenias, coagulopathy, hepatitis / liver failure, and if there is central nervous system involvement, altered mental status, neurologic deficits, and seizures.

Diagnosing HLH
The diagnosis of HLH is often difficult. The symptoms of HLH may mimic that of infections or malignancies. Additionally, HLH is often observed in these settings, and can also occur in patients with rheumatologic disorders.
Laboratory evaluations can help with the diagnosis of HLH. A CBC should be done to look for cytopenias (nearly universal), and a routine liver panel should be performed to screen for hepatitis. Blood levels of ferritin (usually extremely elevated), soluble IL-2 receptor (elevated), soluble CD163 (elevated), fibrinogen (decreased), and triglycerides (elevated) should be measured. Cerebrospinal fluid analysis may show evidence of pleocytosis, haemophagocytosis and elevated protein. Brain MRI may show evidence of HLH. Bone marrow aspirates and biopsies may show evidence of haemophagocytosis (macrophage engulfment of other cells). Laboratory, radiologic, and pathologic studies should be performed to evaluate for associated infections or malignancies.

Genetic Testing for HLH
In many cases, a genetic disorder underlies HLH. Some genetic forms of HLH are grouped as familial Haemophagocytic lymphohistiocytosis, and include mutations affecting PRF1, MUNC13-4, STXBP2, and STX11.
Mutations in RAB27a cause Griscelli syndrome, a related disorder that may or may not be associated with pigmentary defects. Mutations in genes that are important for granule mediated lymphocyte cytotoxicity are often found.
Mutations in SH2D1A / SAP cause X-linked lymphoproliferative disease (XLP), a related disorder characterized by HLH, lymphoma and hypogammaglobulinemia.
Mutations in XIAP / BIRC4 cause an X-linked form of familial HLH that is often referred to as XLP2.
Defects in LYST cause Chediak-Higashi syndrome, another related disorder characterized by HLH, pigmentary, and neutrophil defects.
Specialized blood tests can rapidly screen patients for many of the genetic forms of HLH. Flow cytometric testing is available to screen for perforin, XIAP and SAP protein deficiencies. A functional assay to measure degranulation of NK cells is available (termed a “CD107a assay” in our laboratory) and detects patients with defects in the genes involved in degranulation (Munc 13-4, STXBP2, STX11, Rab27a and Lyst).

HLH Treatment
Once a diagnosis of HLH is established, treatment should be started immediately. The HLH-2004 protocol was based on the HLH-94 protocol with minor changes such as cyclosporin, an immunosuppressant drug, being started at the onset of therapy rather than week #8. This protocol has been widely accepted internationally and is used in numerous countries on all continents but should still be considered experimental.
While patients are undergoing treatment, efforts should be made to determine if there is a genetic defect present. Screening tests may help to guide genetic testing in a logical manner. If a genetic defect is observed, curative treatment with allogeneic hematopoietic cell transplantation should be considered. In the absence of a genetic diagnosis, transplant should also be considered for young patients and those with a family history, recurrent clinical phenotype, or functional laboratory studies suggesting an inherited defect in lymphocyte cytotoxicity.
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