Background: Macrophage activation syndrome (MAS) in adults, also called reactive haemophagocytic syndrome or haemophagocytic lymphohistiocytosis, is the result of inappropriate proliferation and activation of the mononuclear phagocytic system secondary to an underlying disease. Persistent high levels of inflammatory cytokines with impaired cytotoxic capacity of T-lymphocytes and natural killer cells seem to be the main trigger of the syndrome. There are a variety of diseases that can lead to fulminant uncontrolled MAS, mainly viral infections and conditions of immunologic dysregulation such as Systemic Lupus Erythematodes, Morbus Still and neoplastic disorders. Despite the variety of associated diseases, the clinical presentation is uniform with high fever, splenomegaly, lymphadenopathy, hepatomegaly, rash and neurologic abnormalities. MAS is associated with substantial morbidity and mortality. Beside the clinical presentation, extreme elevation of plasma markers for macrophage hyperactivation are mandatory in diagnosing and monitoring MAS (hyperferritinemia, and extreme elevation of neopterin and sIL2R), whereas the phenomenon of hemophagocytosis (±cytopenias) is more variable. Different therapeutic strategies including high-dose steroids, intravenous immunoglobulin (IVIG) [

Emmenegger U, et al. American Journal of Haematology 2001;68:4–10
] and intravenous etoposide (VP16)[
Imashuku S, et al. Journal of Clinical Oncology 2001;19:2665–267
] have been reported to induce remissions, but tend to be incomplete and of short duration. These treatments are mainly based on studies in children with familial haemophagocytic lymphohistiocytosis and have considerable side-effects. The optimal treatment-approach in adults with MAS remains unclear. Faced with high mortality of MAS at our institution, we accepted VP16 as a paticularly important component of therapy but were struck by fast and live threatening relapses during neutropenic episodes following classical pulse-application of VP16 (2x150mg/m²/d x 2/week). We initiated oral low dose VP16 in refractory RHS and observed substantial effects.

Methods and Patients: Our treatment concept was that of uninterrupted macrophage mitigation by continuous low-dose oral VP16 after a first un- or only partially successful episode of high-dose methylprednisolone or IVIG. In the present study we describe the effect of low dose oral VP16 after a first episode treated with high-dose methylprednisolone or IVIG in 3 patients with relapsing or resistant RHS. Close monitoring of cytokine activation was performed by serial measurements of ferritin, sIL2R, transcobalamin II and neopterin (at least twice weekly). 2 of our patients suffered from recurrent MAS in the context of chronic active Epstein-Barr virus infection, 1 patient showed 2 episodes of MAS secondary to Morbus Still. VP16-treatment was dosed at diurnal 50mg for 3 days followed by 15–20mg daily avoiding neutropenic episodes.

Results: During the time of observation (4 years) we have ascertained a total of 9 episodes of MAS, 3 of them classified as severe (admission to intensive care unit). 4 episodes of MAS have been managed by oral VP16 exclusively. Decrease of cytokine activation and clinical outcome in episodes treated with oral VP16 proofed to be superior to the other treatment-strategies.

Conclusion:Compared to steroids and IVIG, strictly monitored long-term low-dose oral VP16 (for several weeks to months) seems to be a safe and most effective treatment strategy in patients with life-threatening reactive MAS.

Topics:
epstein-barr virus infections, etoposide, macrophage activation syndrome, immunoglobulins, intravenous, cytokine, methylprednisolone, neopterin, neutropenia, steroids, adverse effects

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2005, The American Society of Hematology
2004
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