ReviewHemophagocytic syndromes
Section snippets
Classification and terminology of HLH
HLH occurs in all age groups. It is not a single disease but a clinical syndrome that can be encountered in association with a variety of underlying conditions leading to the same characteristic inflammatory phenotype (Fig. 1).
Clinical symptoms and laboratory findings
Prolonged fever, hepatosplenomegaly and cytopenias are the cardinal symptoms of HLH. Lymphadenopathy, rash, icterus or neurological symptoms such as seizures or cranial nerve palsies are less frequent. Characteristic laboratory values include high levels of triglycerides, ferritin, transaminases, bilirubin and LDH and a low fibrinogen.1, 9, 10, 16 The alpha chain of the soluble interleukin-2 receptor (sCD25) is a valuable disease marker because of constantly increased levels during active HLH.17
Genetics and pathophysiology
Upon triggering of the immune system with an (infectious) agent, histiocytes (macrophages and dendritic cells), NK cells and CTLs are activated and mutually stimulate each other. This concerted action leads to killing of the infected cell, removal of antigen and termination of the immune response. Defective cytotoxic activity not only impairs the elimination of cellular targets expressing antigens, but also the down-regulation of the immune response. Sustained immune activation with
Macrophage activation syndrome
The macrophage activation syndrome (MAS), now considered a special form of HLH, occurs in children and adults with autoimmune diseases, especially systemic onset juvenile rheumatoid arthritis (sJRA) or adult-onset Still‘s disease, but also lupus erythematodes or other entities.32, 33 MAS is estimated to occur in up to 7% of patients with sJRA;34 mortality is between 10–20%.
In publications dealing with HLH in adults, the term (reactive) macrophage activation syndrome is often used as a synonym
Diagnostic criteria and differential diagnosis
In 1991 the HLH Study Group of the Histiocyte Society published the first diagnostic guidelines for HLH. The diagnostic criteria were recently revised41 and are shown in Table 2.
When a patient presents with prolonged fever unresponsive to antibiotics, hepatosplenomegaly and cytopenias, HLH as differential diagnosis should be considered. Minimal diagnostic requirements are a complete blood count, liver enzymes, bilirubin, triglycerides, ferritin and a coagulation profile including fibrinogen.
Treatment and prognosis
Life-threatening hyperinflammation, caused by excessive levels of cytokines, can be treated by corticosteroids which are cytotoxic for lymphocytes and inhibit expression of cytokines and differentiation of dendritic cells. Since dexamethasone crosses the blood brain barrier better than prednisolone it is the preferred drug in pediatric protocols. In MAS high-dose prednisolone (30mg/kg × 3days) is often used with good response.34 Cyclosporin A, affecting T-lymphocyte activation and macrophage
Concluding remarks
In patients with prolonged fever, unresponsive to antibiotics, together with pronounced hepatosplenomegaly and cytopenias, the differential diagnosis of HLH should be considered.
Characteristic laboratory changes such as high ferritin and triglycerides, as well as low fibrinogen support the diagnosis. The progressive, life-threatening symptoms of hyperinflammation are conditioned by an inherited or acquired immune defect leading to the inadequate control of an infectious agent and to the failure
References (51)
- et al.
Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations
Blood
(2002) - et al.
Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis
Hematol Oncol Clin North Am
(1998) - et al.
Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis
Am J Med
(1983) - et al.
Peripheral T-cell lymphoma associated with hemophagocytic syndrome
Blood
(1990) - et al.
Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome
Blood
(2000) - et al.
Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis
Hematol Oncol Clin North Am
(1998) - et al.
Elevated soluble interleukin-2 receptor in childhood hemophagocytic histiocytic syndromes
Blood
(1989) - et al.
Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell-induced apoptosis
Blood
(2002) - et al.
Hypercytokinemia in familial hemophagocytic lymphohistiocytosis
Blood
(1991) - et al.
An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder
Blood
(2004)