Hemophagocytic lymphohistiocytosis (HLH) is an uncommon disorder causing immune dysfunction in infants and young children. Many patients have an underlying immune disorder, although in some patients the underlying disorder is not known. Manifestations may include lymphadenopathy, hepatosplenomegaly, fever, and neurologic abnormalities. Diagnosis is by specific clinical and testing (genetic) criteria. Treatment is usually with chemotherapy and, in refractory cases or in cases with a genetic cause, hematopoietic stem cell transplantation.

HLH is characterized by

• High levels of cytokines (eg, IL-1, IL-2; TNF-α; interferon [INF]-γ; soluble IL-6, IL-10, IL-12; granulocyte-macrophage colony stimulating factor [GM-CSF])
• Uncontrolled proliferation and activation of cytotoxic T cells, natural killer cells, and macrophages in multiple tissues

Certain aspects of immune function, such as natural killer cell and cytotoxic T-cell activity, are abnormal.

HLH is uncommon. It affects mostly infants < 18 mo. HLH can be

• Familial (primary)
• Acquired (secondary)

In both forms, genetic abnormalities, clinical manifestations, and outcomes tend to be similar. Acquired HLH can be associated with other immune disorders (eg, leukemias, lymphomas, SLE, RA, polyarteritis nodosa, sarcoidosis, progressive systemic sclerosis, Sjögren's syndrome, Kawasaki disease) and can occur in kidney or liver transplant recipients. Acquired HLH may be secondary to other disorders or to immunosuppressive regimens used to treat them or possibly to infections.

Symptoms and Signs

Common early manifestations include fever, hepatomegaly, splenomegaly, rash, lymphadenopathy, and neurologic abnormalities (eg, seizures, retinal hemorrhages, ataxia, altered consciousness or coma). Bone lesions may occur, and clinical manifestations may mimic child abuse.

Diagnosis

• Specific clinical and testing criteria

HLH is suspected in children with unexplained recurrent infections and typical laboratory abnormalities (cytopenias, coagulopathy, abnormal liver function test results, high serum ferritin levels) or with typical symptoms and signs.

Diagnosis requires the presence of > 5 of the following criteria:

• Fever (peak temperature of > 38.5° C for > 7 days)
• Splenomegaly (spleen palpable > 3 cm below costal margin)
• Cytopenia involving > 2 cell lines (Hb < 9 g/dL, absolute neutrophil count < 100/μL, platelets < 100,000/μL)
• Hypertriglyceridemia (fasting triglycerides > 2.0 mmol/L or > 3 standard deviations [SD] more than normal value for age) or hypofibrinogenemia (fibrinogen < 1.5 g/L or > 3 SD less than normal value for age)
• Hemophagocytosis (in biopsy samples of bone marrow, spleen, or lymph nodes)
• Low or absent natural killer cell activity
• Serum ferritin > 500 μg/L plus elevated soluble IL-2 (CD25) levels (> 2400 U/mL or very high for age)

Clinical Calculator

Because some of these tests may not be widely available and HLH is uncommon, patients are usually referred to specialized centers for evaluation.

Treatment

• Hematopoietic stem cell transplantation and chemotherapy

Treatment should be started if the disorder is suspected, even if not all diagnostic criteria are fulfilled. Patients are usually treated by a pediatric hematologist and in a referral center experienced in treating patients with HLH. Depending on the presence of factors such as a family history of HLH, coexisting infections, and demonstrated immune system defects, treatment can involve combinations of hematopoietic stem cell transplantation, dexamethasone, cyclosporine, etoposide, and methotrexate.

Last full review/revision November 2009 by Jeffrey M. Lipton, MD, PhD