Diagnosis

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). Additionally, the following findings may present: fibrinogen (decreased) and triglycerides (elevated). Cerebrospinal fluid analysis may show evidence of pleocytosis, hemophagocytosis and elevated protein. Brain MRI may show variable evidence of HLH when reviewed by a neuroradiologist knowledgeable with this condition. Bone marrow aspirates and biopsies may show evidence of hemophagocytosis (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 hemophagocytic lymphohistiocytosis, and include patient with 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).

Expert Services and Advice

If you suspect a patient has HLH, laboratories at Cincinnati Children’s offer expert testing and clinical interpretation.

All aspects of the HLH diagnostic process are supervised by the leaders of the Diagnostic Immunology Laboratory and the Molecular Genetics Laboratory who are part of the HLH Center of Excellence. We offer expert advice regarding appropriate tests to order for patients, and the interpretation of results as they relate to treatment of the patient.