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Hemophagocytic Lymphohistiocytosis (HLH)

By Jeffrey M. Lipton, MD, PhD, Professor of Pediatrics and Molecular Medicine;Professor;Chief, Hematology/Oncology and Stem Cell Transplantation, Hofstra Northwell School of Medicine, Hempstead, NY;The Center for Autoimmune and Musculoskeletal Disease, Feinstein Institute for Medical Research;Cohen Children’s Medical Center of New York ; Carolyn Fein Levy, MD, Assistant Professor, Hofstra Northwell School of Medicine

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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.

Hemophagocytic lymphohistiocytosis (HLH) is uncommon. It affects mostly infants < 18 mo. It involves a defect in targeted killing and the inhibitory controls of natural killer and cytotoxic T cells, resulting in excessive cytokine production and accumulation of activated T cells and macrophages in various organs. Cells in the bone marrow and/or spleen may attack RBCs, WBCs, and/or platelets.

HLH can be

  • Familial (primary)

  • Acquired (secondary)

HLH is diagnosed when patients fulfill at least 5 of the criteria described below or have a mutation in a known HLH-associated gene.

Acquired HLH can be associated with infections (eg, Epstein-Barr virus, cytomegalovirus, or others), cancer (eg, leukemias, lymphomas), immune disorders (eg, SLE, RA, polyarteritis nodosa,sarcoidosis, progressive systemic sclerosis, Sjögren syndrome, Kawasaki disease) and can occur in kidney or liver transplant recipients.

In both forms, genetic abnormalities, clinical manifestations, and outcomes tend to be similar.

Symptoms and Signs

Common early manifestations of hemophagocytic lymphohistiocytosis include fever, hepatomegaly, splenomegaly, rash, lymphadenopathy, and neurologic abnormalities (eg, seizures, retinal hemorrhages, ataxia, altered consciousness or coma).

Diagnosis

  • Clinical and testing criteria

Hemophagocytic lymphohistiocytosis can be diagnosed if there is a mutation in a known causative gene or if at least 5 of 8 diagnostic criteria are met:

  • 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

  • Elevated soluble interleukin-2 (CD25) levels (>2400 U/mL or very high for age)

Genetic mutations associated with HLH include

  • PRF1

  • UNC13D

  • STX11

  • STXBP2

  • RAB27

  • XLP

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

Treatment

  • Chemotherapy, cytokine inhibitors, immune suppression, and sometimes hematopoietic stem cell transplantation

Treatment for hemophagocytic lymphohistiocytosis 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. Treatment depends on the presence of factors such as a family history of HLH, coexisting infections, and demonstrated immune system defects. Treatment for HLH may include cytokine inhibitors, immune therapy, chemotherapy, some combination of these, and possibly stem cell transplantation.