Haemophagocytic syndromes in adults: current concepts and challenges ahead.

Haemophagocytic syndrome (HS), also referred to as haemophagocytic lymphohistiocytosis or macrophage activation syndrome, comprises a heterogeneous group of disorders featuring sepsislike characteristics typically combined with haemophagocytosis, hyperferritinemia, hypercytokinemia and variable cytopenias, often resulting in fatal multiple organ failure. The availability of widely accepted diagnostic and therapeutic guidelines for the hereditary, paediatric forms of HS has improved outcome and lead to a better pathophysiological understanding. Although similar, reactive (secondary) HS in adults are distinct from childhood forms. Limited awareness of this type of disorder and the absence of clinical guidelines are to blame for delayed diagnosis and dire prognosis in many cases of HS in adults. Moreover, the underlying mechanisms of adult HS remain to be unravelled yet. We summarise general features of HS and discuss particular characteristics of this disorder inadults. Furthermore, we describe a simple screening and diagnostic algorithm based on serum markers of macrophage activation (ferritin, soluble CD163 and soluble CD25) and morphological evidence of haemophagocytosis. Application of this strategy might be instrumental for recruiting patients for clinical studies, early diagnosis and hence improved prognosis. Indeed, there is evidence that a subgroup of patients with systemic inflammatory response syndrome presenting with signs of macrophage activation benefit from early administration of intravenous immunoglobulins. Clinical studies are needed to validate our diagnostic approach and to establish well defined prognostic and therapeutic algorithms. Finally, we will discuss whether similar processes contribute to HS in adults compared to childhood forms.

Reactive macrophage activation syndrome: a simple screening strategy and its potential in early treatment initiation.

QUESTIONS UNDER STUDY: starting treatment of reactive macrophage activation syndromes as early as possible (rMAS, haemophagocytic lymphohistiocytosis), e.g., with intravenous immunoglobulins (IVIG), seems to be essential for optimal outcome. However, there is no diagnostic gold standard which reliably indicates need for early treatment. We used a simple screening strategy consisting of serum ferritin measurements and/or morphological assessment of haemophagocytosis and compared the studied patient population with published series. METHODS: Retrospective analysis of clinical and laboratory data of 57 patients experiencing 60 episodes of rMAS. RESULTS: Screening by serum ferritin measurements and/or morphological assessment of haemophagocytosis of patients presenting with a systemic inflammatory response syndrome (SIRS) indicates that rMAS might be considerably more frequent than stated in the literature. Serum ferritin exceeded >10,000 microg/L in 91% rMAS episodes. Although the patient population studied was otherwise similar in most aspects to the published rMAS series, the fact that 40% of patients fulfilled the criteria for Still's disease (SD) as the disorder underlying rMAS is remarkable and questions the distinct nature of the two diseases. IVIG responders and non-responders did not differ regarding their initial characteristics with exception to the timepoint of IVIG administration, confirming the importance of early treatment initiation. Malignancy-associated rMAS however, has a poor prognosis and seems to be refractory to manipulation with IVIG in most instances, even when responding initially. CONCLUSIONS: rMAS has to be considered in patients with a SIRS- or SD-like clinical presentation. Hyperferritinaemia >or=10,000 microg/l seems to be a good marker for defining patients with or at risk for developing rMAS and should be completed with a morphological assessment of haemophagocytosis. The perception of acute SD and rMAS as two distinct entities has to be questioned at least in a subgroup of patients.

Macrophage activating syndrome is associated with lobular hepatitis and severe bile duct injury with cholestasis.

Macrophage activating syndrome (MAS) is a rare hematological disorder associated with uncontrolled systemic T-cell activation. Persistent fever, fatigue and hepatosplenomegaly are frequent clinical manifestations, whereas hyperferritinemia, elevated serum lactate dehydrogenase levels and cytopenia are key criteria for the diagnosis of MAS. The nature of liver pathology in MAS has been partially elucidated but destructive biliary lesions have been rarely described. This report illustrates four cases of MAS developing marked cholestasis, leading to one case of biliary cirrhosis necessitating liver transplantation. Histologically, liver involvement was characterized in all cases by acute lobular hepatitis, marked hepatocyte apoptosis and small bile duct injury similar to the vanishing bile duct syndrome. Immuno-histological studies showed that the inflammatory changes and bile duct lesions were dominated by the presence of activated macrophages and T-cells, in particular CD8+ lymphocytes, and in part NK-cells. These findings suggest that in MAS, various T-cell triggers such as infection, autoimmune disease and malignancy might result in the release of cytokines, which in turn activate macrophages to trigger a systemic acute phase response and local tissue damage. This communication suggests that a macrophage, T- and NK-cell network is operational in the pathogenesis of the cholangiocyte, hepatocyte and sinus endothelial cell damage in MAS.