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 congenital (familial or primary HLH, observed mainly in children; mild types of the disease may be diagnosed in adults) or acquired (secondary HLH in the setting of severe infection [most commonly Epstein-Barr virus], autoimmune disease, or malignancy [particularly lymphoma]; 6%-18% of cases are idiopathic). Hypersecretion of proinflammatory cytokines causes a pathologic inflammatory reaction that leads to generalized organ damage.
A subtype of HLH is macrophage activation syndrome (MAS) (see Systemic Lupus Erythematosus), which is differentiated from HLH on the basis of high serum C-reactive protein levels. MAS develops most frequently in the course of Still disease, systemic lupus erythematosus, and in patients after bone marrow transplantation.
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. Untreated disease is 100% fatal.
1. Laboratory tests:
1) Complete blood count: 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).
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.
3) Peripheral cytopenia affecting ≥2 out of 3 lineages (hemoglobin <9 g/dL, platelet count <100,000/microL, neutrophil count <1000/microL).
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, or lymph nodes.
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.
In patients with ferritin levels >2000 microg/L, fulfillment of only 4 criteria may be sufficient for diagnosis.
Another scoring system, HScore, available online at saintantoine.aphp.fr, can be used to estimate an individual’s risk of having acquired HLH.
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: Reticulocyte count, erythrocyte sedimentation rate, biochemical tests (lactate dehydrogenase, aminotransferase, bilirubin, creatinine, urea/blood urea nitrogen, C-reactive protein), coagulation parameters, serum protein electrophoresis, serum immunoglobulin levels, antiglobulin (Coombs) tests.
2) Virologic studies, including diagnostics for Epstein-Barr virus infection (immunohistochemistry for latent membrane protein 1 in biopsy).
3) Neurologic examination. In patients with CNS symptoms, perform also 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.
5) Cytologic and histologic examination of bone marrow.
6) Other studies relevant to the features observed in the patient, including diagnostics for lymphoma.
1. Treatment of HLH: Use the HLH-2004 regimen (etoposide, dexamethasone, cyclosporine [INN ciclosporin]) for 8 weeks, also in patients with relapse. In patients with CNS involvement, administer intrathecal methotrexate. In treatment-resistant patients, consider use of lymphoma chemotherapy regimens and alemtuzumab, as well as anti-interleukin-6 monoclonal antibodies (if available). In patients with HLH caused by lymphoma or other cancers, replace the HLH-2004 regimen with a standard regimen used in the causative malignancy. In inherited, refractory, or recurrent disease, allogeneic hematopoietic stem cell transplantation 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.
Despite treatment, this disorder has a very high mortality rate in adults (up to 50%-75%).