Hemophagocytic Lymphohistiocytosis Hemophagocytic Syndromes

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Hemophagocytic lymphohistiocytosis (HLH) falls into two categories:

1. Familial hemophagocytic lymphohistiocytosis (FHLH) (familial or sporadic): This is an autosomal recessive disease that affects immune regulation. Although it is commonly termed familial HLH, because the disease has an autosomal recessive inheritance, sporadic cases with no obvious family inheritance occur. FHLH may be triggered by infections.

2. Nonfamilial HLH: A lymphohistiocytic proliferation with hemophagocytosis may also develop from marked immunological activation during viral, bacterial, and parasitic infections (see Infection-Associated Hemophagocytic Lymphohistiocytosis section). This may also be associated with malignancies, prolonged administration of lipids, rheumatoid arthritis (macrophage activation syndrome), immune deficiencies associated with cytotoxic T- and/or NK-cell dysfunction such as DiGeorge syndrome (del 22q11.2), Chediak-Higashi syndrome, Griscelli syndrome,* X-linked lymphoproliferative disease (XLP), and lysinuric protein intolerance (LPI).

Table 22-13 lists the diagnostic guidelines for HLH. Note that there is no specific diagnostic feature for primary HLH (FHLH). For this reason, when the index of suspicion is strong for primary HLH, treatment may be started before extensive disease activity causes irreversible organ damage and the likelihood of a response to therapy decreases.

Familial Hemophagocytic Lymphohistiocytosis

Pathophysiology, Immunology, and Genetics

In the absence of perforin activity, the resulting inability to kill infected target cells results in sustained NK- and cytolytic T-cell (CTL) activity. This, in turn, results in the

*Type 2; mutation in RAB27A[15q21], decreased T- and NK-cell function, hypogammaglobulinemia, and partial albinism.

Table 22-13. Diagnostic Guidelines for Hemophagocytic Lymphohistiocytosis"

Clinical criteria


Splenomegalyb Laboratory criteria

Cytopenia affecting at least two of three lineages in the peripheral blood6: Hemoglobin (<90 g/L) Platelets (<100 x 109/L) Neutrophils (<1.0 x 109/L)

Hypertriglyceridemia and/or hypofibrinogenemia6 (fasting triglycerides, >2.0 mmol/L or 3 SD of the normal value for age; fibrinogen, <1.5 g/L or <3 SD) Histopathologic criteria

Hemophagocytosis in bone marrow or spleen or lymph nodes6

No evidence of malignancy

"If hemophagocytic activity is not proven at the time of presentation, further search for hemophagocytic activity is encouraged. If the bone marrow specimen is not conclusive, material should be obtained from other organs, especially lymph nodes or spleen (fine-needle aspiration biopsy). Serial marrow aspirates over time may also be helpful.

The following findings may provide strong supportive evidence for the diagnosis:

1. Spinal fluid pleocytosis (mononuclear cells)

2. Histologic picture in the liver resembling chronic persistent hepatitis

3. Low natural killer cell activity.

Other abnormal clinical and laboratory findings consistent with the diagnosis are cerebromeningeal symptoms, lymph node enlargement, jaundice, edema, skin rash, hepatic enzyme abnormalities, hyperferritinemia, hypoproteinemia, hyponatremia, spinal fluid protein T, very low density lipoprotein (VLDL) T, high-density lipoprotein (HDL) 4, circulation soluble interleukin-2 receptor T.

6All criteria required for the diagnosis of HLH. In addition, the diagnosis of FHLH is justified by a positive family history, and parental consanguinity is suggestive.

From Henter JI, Arico M, Elinder G, Imashuku S, Janka G. Familial hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998;12:417-33, with permission.

overexpression of inflammatory cytokines (soluble IL-2 receptor, IL-6, TNF-a, IL-10, and IL-12) leading to excessive macrophage activation, dissemination, and organ infiltration and the signs, symptoms, and laboratory abnormalities that characterize HLH.

Impaired NK-cell activity is key to the diagnosis. FHLH is inherited as an autosomal recessive disorder. FHLH type 1, in linkage with the 9q21.3 locus, represents approximately 10% of the cases and can be recognized by impaired NK-cell function not associated with the absence of perforin expression. The absence of intracytoplas-mic perforin may be used as a reliable marker in the 20-40% of patients with familial HLH type 2 associated with the 10q21-22 mutations in the gene at chromosome 10q22 resulting in perforin gene (PRF1) mutations. Perforin functions by perforating the cytolytic target cell membrane, allowing for the entry of granzymes that in turn initiate the apoptotic cell death pathway. The pathways leading to the synthesis of perforin, subcellular compartmentalization, and directional targeting and release of cytolytic granules all represent potential points that could be mutated and contribute to different genetic causes of inherited HLH syndromes. One such is the description of mutations in the Munc 13-4 gene, which is essential for cytolytic granule fusion. Inactivating mutations in this gene, located at chromosome 17q25, have now been shown to cause familial HLH, termed FHLH type 3. Those patients with absent per-forin expression should undergo PRF1 and more recently described Munc 13-4 (FHLH type 3) mutation analysis.

A substantial proportion of familial cases of HLH are genetically completely uncat-egorized. Patients with an infection-associated HLH may have transiently impaired

NK activity; thus, mutation analysis will distinguish these cases from familial HLH. In the absence of a positive mutation analysis, réévaluation of NK function after successful treatment should be undertaken.

In summary, a wide array of immune dysfunction may result in defective NK and CTL target cell killing, resulting in the failure to eliminate infected cells, which, in turn, permits a sustained inflammatory response complete with excessive cytokine production and sustained systemic macrophage activation that characterizes a final pathway of HLH.

Clinical Features

1. The age of onset is less than 1 year of age in 70% of cases. There is no known upper age limit for the onset of disease.

2. Signs and symptoms of FHLH:

a. Fever (91%), splenomegaly (98%), and hepatomegaly (94%) are the most common early findings.

b. Lymph node enlargement (17%), skin rash (6%), and neurologic abnormalities (20%) may also occur. Neurologic findings include irritability, bulging fontanel, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, blindness, and unconsciousness.

c. Multisystem involvement includes lungs, bone marrow, and leptomeninges. Occasionally, ocular, heart, skeletal muscles, and kidney involvement have been noted.


Patients should be treated as per modern protocols (HLH 2004) according to the Histiocyte Society.* Nonfamilial disease is treated in a similar manner. The following treatment protocol has been utilized:

1. Dexamethasone 10 mg/m2/day for 2 weeks followed by a decrease every 2 weeks to 5 mg/m2, 2.5 mg/m2, and 1.25 mg/m2 for a total of 6 weeks

2. Etoposide IV (150 mg/m2 IV 2-hour infusions daily) twice weekly for 2 weeks, then weekly

3. Cyclosporine A 3-5 mg/kg/day by continuous IV infusion starting week 8 to reach a blood trough level of 150-200 ng/mL and switching to oral administration of 6-10 mg/kg/day in two divided doses

4. Intrathecal methotrexate (IT MTX), age-adjusted doses of IT MTX weekly for 3-6 weeks as follows if there are progressive neurologic symptoms or if abnormal cells persist in the CSF:

Age (years)

IT MTX dose (mg)


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