Elsevier

Blood Reviews

Volume 21, Issue 5, September 2007, Pages 245-253
Blood Reviews

Review
Hemophagocytic syndromes

https://doi.org/10.1016/j.blre.2007.05.001Get rights and content

Summary

Hemophagocytic syndromes (hemophagocytic lymphohistiocytosis, HLH) represent a severe hyperinflammatory condition with the cardinal symptoms prolonged fever, cytopenias, hepatosplenomegaly, and hemophagocytosis by activated, morphologically benign macrophages. Biochemical markers include elevated ferritin and triglycerides, and low fibrinogen. Whereas in children several inherited immune deficiencies may lead to this syndrome, most adults with HLH have no known underlying immune defect. Nevertheless, impaired function of natural killer (NK) cells and cytotoxic T-cells (CTL) is characteristic for both genetic and acquired forms of HLH. Frequent triggers are infectious agents, mostly viruses of the herpes group. Malignant lymphomas, especially in adults, may be associated with HLH. A special form of HLH in rheumatic diseases is called macrophage-activation syndrome.

Initially HLH may masquerade as a normal infection since all symptoms, even though less pronounced, may also be found in immune competent patients. Patients with HLH, however, cannot control the hyperinflammatory response which, if untreated, is fatal in genetic cases and in a high percentage of acquired cases. Awareness of the clinical symptoms and of the diagnostic criteria of HLH is important to start life-saving therapy with immunosuppressive/ immunomodulatory agents in time.

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

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