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Hemophagocytic Lymphohistiocytosis (HLH)


Jeffrey M. Lipton

, MD, PhD, Zucker School of Medicine at Hofstra/Northwell;

Carolyn Fein Levy

, MD, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

Reviewed/Revised Dec 2021

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 months but can occur at any age. 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 red blood cells, white blood cells, 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 Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more Infectious Mononucleosis , cytomegalovirus Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more , or others), cancer (eg, leukemias Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more , lymphomas Overview of Lymphomas Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma Non-Hodgkin lymphoma See table . Lymphomas were once... read more ), immune disorders (eg, systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more Systemic Lupus Erythematosus (SLE) , rheumatoid arthritis Rheumatoid Arthritis (RA) Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Rheumatoid Arthritis (RA) , polyarteritis nodosa Polyarteritis Nodosa (PAN) Polyarteritis nodosa is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries and occasionally affects small muscular arteries, resulting in secondary tissue... read more , sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more Sarcoidosis , progressive systemic sclerosis Systemic Sclerosis Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus... read more Systemic Sclerosis , Sjögren syndrome Sjögren Syndrome Sjögren syndrome is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the mouth, eyes, and other mucous membranes ... read more Sjögren Syndrome , Kawasaki disease Kawasaki Disease Kawasaki disease is a vasculitis, sometimes involving the coronary arteries, that tends to occur in infants and children between the ages of 1 year and 8 years. It is characterized by prolonged... read more Kawasaki Disease ) and can occur in kidney or liver transplant recipients.

In both familial and acquired forms, clinical manifestations are similar.

Symptoms and Signs of HLH

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

Diagnosis of HLH

  • 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 based on HLH-2004 protocol (1 Diagnosis reference 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... read more ) 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 (hemoglobin < 9 g/dL [90 g/L], absolute neutrophil count < 100/mcL [0.10 × 109/L], platelets < 100,000/mcL [100 × 109/L])

  • Hypertriglyceridemia (fasting triglycerides > 177 mg/dL [2.0 mmol/L] or > 3 standard deviations [SD] more than normal value for age) or hypofibrinogenemia (fibrinogen < 150 mg/dL [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 ng/mL (> 1123.5 pmol/Lng/mL)

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

Genetic mutations associated with HLH include

  • PRF1

  • RAB27

  • STX11

  • STXBP2

  • UNC13D

  • XLP

Because some of these tests may not be widely available and HLH is uncommon, patients are usually referred to specialized centers for evaluation. Genetic testing is recommended to look for primary HLH mutations as well as mutations that characterize immune dysregulation. Familial and acquired forms are differentiated only by family history.

Diagnosis reference

  • 1. Henter JI, Horne A, Aricó M, et al: HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48(2):124–131, 2007. doi: 10.1002/pbc.21039

Treatment of HLH

  • 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 Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more .

A response to early initiation of anakinra (IL1 antagonist) in patients with secondary HLH has been reported and may allow for avoidance of intensive chemotherapy but requires further investigation (1 Treatment reference 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... read more ). Ruxolitinib (a JAK-STAT pathway inhibitor) for upfront treatment of HLH is being explored in a clinical trial sponsored by the North American Consortium for Histiocytosis (NACHO).

Emapalumab, an interferon gamma–blocking monoclonal antibody, is available for patients with refractory, recurrent, or progressive HLH or with an intolerance to conventional therapy.

Treatment reference

  • 1. Bami S, Vagrecha A, Soberman D, et al: The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 67(11):e28581, 2020. doi: 10.1002/pbc.28581

Key Points

  • Hemophagocytic lymphohistiocytosis (HLH) is an uncommon rare disorder and usually affects infants < 18 months.

  • HLH can be familial (inherited) or acquired.

  • Diagnose HLH if the patient has at least 5 of 8 published diagnostic criteria or if the patient has a known mutation associated with HLH.

  • Treat with chemotherapy, cytokine inhibitors, immune suppression, and sometimes hematopoietic stem cell transplantation.

More Information

The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

Drugs Mentioned In This Article

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Jakafi, Opzelura
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