Hemophagocytic Lymphohistiocytosis (HLH)

Definition, Etiology, PathogenesisTop

Hemophagocytic lymphohistiocytosis (HLH) is a disturbance of immune regulation caused by proinflammatory cytokines in a person with a concomitant dysfunction of immune cells (natural killer [NK] cells and cytotoxic T cells). The dysfunction may be primary (congenital) or secondary (acquired) HLH. Primary HLH is most often observed in children; mild types of the disease may be diagnosed in adults. Secondary HLH is seen in the setting of infection (most commonly Epstein-Barr virus [EBV]), malignancy (particularly lymphoma), autoimmune disease, or may be drug induced (eg, CAR-T/BiTE therapies or checkpoint inhibitors) or idiopathic (6%-18% of cases). Hypersecretion of proinflammatory cytokines causes a pathologic inflammatory reaction that leads to generalized organ damage.

A variety of hematologic malignancies may present as HLH, including highly aggressive T cell lymphomas.

A subtype of secondary HLH is macrophage activation syndrome (MAS) (see Systemic Lupus Erythematosus), which occurs in the context of a rheumatologic disorder. MAS develops rarely in the course of systemic juvenile idiopathic arthritis (previously known as Still disease), adult-onset Still disease, systemic lupus erythematosus, and dermatomyositis.

Clinical Features and Natural HistoryTop

Individual differences in clinical manifestations exist, which may include persistent fever, enlargement of the liver and the spleen, and bleeding disorder; erythematous, papular, or bullous rash, which may be hemorrhagic; effusions in body cavities; and altered mental status. In secondary HLH, symptoms may be specific to a disease or disorder associated with HLH. Untreated disease is 100% fatal.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests:

1) Complete blood count (CBC): Pancytopenia (usually including lymphopenia).

2) Biochemical tests (see Diagnostic Criteria, below).

3) Disseminated intravascular coagulation may be present.

2. Histologic/cytologic studies of bone marrow specimens, the spleen, lymph nodes, and sometimes of other organs or cerebrospinal fluid (CSF) (in patients with central nervous system [CNS] involvement) reveal prominent hemophagocytes. These are macrophages containing phagocytosed red blood cells (RBCs), and sometimes also other cells, for instance, white blood cells or platelets, or their fragments.

3. Other studies are performed for differential diagnosis (see Differential Diagnosis, below).

Diagnostic Criteria

Molecular diagnosis (identification of the causative mutation) or fulfilling ≥5 out of the 8 following criteria (according to the HLH-2004 trial):

1) Fever ≥38.5 degrees Celsius.

2) Splenomegaly.

3) Peripheral cytopenia affecting ≥2 out of 3 lineages (hemoglobin <9 g/dL, platelet count <100×109/L, neutrophil count <1×109/L).

4) Elevated triglyceride levels (fasting triglycerides ≥3 mmol/L [265 mg/dL]) and/or decreased fibrinogen levels (≤1.5 g/L).

5) Elevated ferritin levels (≥500 microg/L).

6) Prominent hemophagocytes found in bone marrow, CSF, lymph nodes, or involved organ tissues.

7) Reduced or absent NK-cell activity (measured by cytotoxicity assays, such as chromium release or flow cytometry, for expression of perforin, granzyme B, or CD107a).

8) sCD25 (alpha chain of the interleukin-2 receptor) levels ≥2400 U/mL.

Increased CSF mononuclear cell and/or elevated protein levels can be strongly supportive. If tissue diagnosis is inconclusive, alternative tissue biopsy and/or serial bone marrow biopsies and aspirate testing can be considered.

Values >10,000 microg/L have increased sensitivity and specificity in children. Ferritin values are often significantly elevated (>7000-10,000 microg/L) in adults, but overall ferritin has poor diagnostic utility in adults. Another scoring system, HScore, available online at saintantoine.aphp.fr, can be used to estimate an individual’s risk of having acquired HLH.

Differential Diagnosis

The most important condition to be differentiated from HLH is sepsis (although these two may also coexist). Other conditions that cause fever, pancytopenia, liver abnormalities, or neurologic findings (eg, hematologic malignancies) should be considered. Conditions with possible elevated ferritin levels include iron overload (repeated RBC transfusions), infections, cancers, rheumatologic/inflammatory disorders (particularly Still disease), liver diseases, and renal failure; however, the negative predictive value of a normal ferritin level for HLH diagnosis remains extremely high.

To differentiate between various causes of abnormalities that serve as diagnostic criteria of HLH, perform the following studies:

1) Laboratory tests (in addition to those included in the diagnostic criteria above): Reticulocyte count, erythrocyte sedimentation rate (ESR), biochemical tests (lactate dehydrogenase, aminotransferase, bilirubin, creatinine, urea/blood urea nitrogen [BUN], C-reactive protein [CRP]), coagulation parameters, serum protein electrophoresis, serum immunoglobulin levels, antiglobulin (Coombs) tests.

2) Virologic studies, including diagnostics for EBV infection (immunohistochemistry for latent membrane protein 1 in biopsy), HIV, and viral hepatitis (types B and C). Given the clinical similarities between HLH and severe sepsis, surveillance bacterial cultures should be performed.

3) Neurologic examination. In patients with CNS symptoms, perform CSF examination including a smear.

4) Ultrasonography and/or computed tomography (CT) of the spleen and the liver, and CT or magnetic resonance imaging (MRI) of the head if indicated. If unremarkable, consider positron emission tomography (PET) to evaluate for occult malignancy.

5) Cytologic and histologic examination of bone marrow and/or other pathologic tissues, such as enlarged lymph nodes or liver biopsy in cases of abnormal liver function tests. Consider consultation with a lymphoma reference pathologist.

TreatmentTop

1. Treatment of HLH: Treatment is usually conducted in a specialized setting. Use the HLH-94 regimen (etoposide, dexamethasone, cyclosporine [INN ciclosporin]) for 8 weeks, also in patients with relapse. In patients with CNS involvement, administer intrathecal methotrexate. Treatment should be adapted to treat underlying disease triggers when known. In patients with HLH caused by lymphoma or other cancers, replace the HLH-94 regimen with a standard regimen used in the causative malignancy. In patients with HLH caused by viral infection, consider virostatics, and if it is associated with EBV, add rituximab. In treatment-resistant patients, additional therapeutic options to consider include the use of lymphoma chemotherapy regimens, anakinra (interleukin [IL]-1 antagonist), alemtuzumab (anti-CD52 antibody), intravenous immunoglobulin (IVIG), anti–IL-6 monoclonal antibodies (if available), emapalumab-lzsg, and off-label ruxolitinib (Janus kinase [JAK] 1/2 inhibitor). In inherited, refractory, or recurrent disease, allogeneic hematopoietic stem cell transplant should be considered. Treatment of MAS: see Systemic Lupus Erythematosus.

2. Symptomatic treatment: Many patients are critically ill and require aggressive therapies to maintain life. Treatments for secondary conditions (such as suspected sepsis) should be administered.

PROGNOSISTop

Despite treatment, this disorder has very high mortality rates in adults (up to 50%-75%). These rates are largely dependent on the underlying pathology (with malignancy-associated HLH having the worst prognosis).