Kuppe et al. Allergy, Asthma & Clinical Immunology 2012, 8:6 http://www.aacijournal.com/content/8/1/6 Table 2 Diagnostic criteria for HLH* (1) Fever (2) Splenomegaly (3) Cytopenia involving two or more cell lines (4) Hypertriglyceridaemia or hypofibrinogenaemia (5) Haemophagocytosis (6) Hepatitis (7) Low or absent natural killer cell activity (8) Serum ferritin level > 500 μg (9) Soluble CD25 (sIL-2 receptor) > 2500 U/ml *according to HLH-2004 criteria (Henter JI et al.). weeks of the initial diagnosis of the syndrome. This syndrome is caused by dysregulated macrophage- lymphocyte interaction, which leads to uncontrolled proliferation of macrophages and CD8+ T-cells with up-regulated release of monokines, mainly of the interleukin-1 family (interleukin-1α and 1β and inter- leukin-18), whereas levels of T-cell–derived cytokines, such as interferon-γ, are much less increased [12]. Re- cently, cell-type specific characteristics of ‘immature antigen presenting cells (APC)’ from patients with MAS have been described. It is known that tumours (espe- cially fibroblasts) can express M-CSF, which could influ- ence the development of immature phagocytic APCs [13]. In our patient, fulminant MAS was present for ap- proximately 3 weeks until the initiation of therapy. The standard definition of HLH requires the presence of at least five of nine clinical criteria. Our patient fulfilled seven of these criteria (Table 2). Additionally, we could find an extramedullary manifestation of MAS, namely a proliferative (Ki-67-positive) histiocytic cell infiltrate in both elbows of the patient. Typically in the acute phase of the cytokine storm, lymphohistiocytic infiltrates can be found in the spleen, lymph nodes and bone marrow [5]. A CD1a staining of the cubital veins remained nega- tive, thus making the diagnosis of Langerhans-cell histio- cytosis unlikely. In the absence of a clinically apparent malignancy, in addition to MAS, the differential diagno- sis for fever with splenomegaly, liver failure and bilat- erally enlarged lymph nodes includes premalignant, inflammatory, infectious, genetic and toxic causes. All of these could be ruled out on the basis of the history and laboratory studies. Acute EBV and CMV infections are associated with fever, pharyngitis, lymphadenopathy and fatigue and would likely have been self-limited. The dif- ferential diagnosis of sarcoidosis was mainly ruled out because no granulomas could be found in any of the bi- opsies. Furthermore, the bone marrow did not show any premalignant, infiltrative or infectious processes. Several treatment options have been reported in the literature for MAS. A treatment protocol from the His- tiocyte Society recommends a therapeutic regimen of Page 5 of 6 Manifestations in the patient described quotidian fever over several weeks hepatosplenomegaly haemoglobin < 9.0 d/dL, no other no yes yes yes 1043 μg/L > 7200 U/ml etoposide, dexamethasone and cyclosporine [14]. In other cases, high-dose steroids, cyclosporine, antihuman thymocyte globulin (ATG), intravenous immune globulin (IVIG), plasma exchange and allogeneic bone marrow transplantation have been described. Recently, treatment with an IL-1 beta receptor antagonist (anakinra) was successful in several cases of severe paediatric rheumatic disease-associated MAS [15,16]. It can be speculated that other immunomodulatory therapies (alemtuzumab, infliximab, daclizumab, selective IL-1 and IL-6 antago- nists) might influence the course of the disease benefi- cially, but clinical trials remain almost impossible due to the rare occurrence of the disease. In summary, we describe the first patient with macro- phage activation syndrome (MAS) and a history of an inflammatory myofibroblastic tumour, which could be controlled by immunosuppressive therapy including steroids and cyclosporine. Consent Written informed consent was obtained from the patient for publication of this case report. Competing interests The authors declare that they have no competing interests. Authors’ contributions BH and JF diagnosed the case and planned the treatment and medical follow up. CK gathered the patient's history and drafted the manuscript and the subsequent revisions. MJ and JF participated in manuscript revision. SW carried out immunohistochemistry. MS carried out FACS and in-vitro studies. All authors read and approved the final manuscript Author details 1Department of Nephrology and Clinical Immunology, University Hospital of the Aachen University of Technology (RWTH), Aachen, Germany. 2Department of Pathology, University Hospital of the Aachen University of Technology (RWTH), Aachen, Germany. 3Department of Experimental Anesthesiology, University Hospital, Ulm, Germany. Received: 5 March 2012 Accepted: 7 May 2012 Published: 20 May 2012 References 1. Ravelli A, Benedetti FD, Martini A, Viola S, Pediatrica C: Clinical and laboratory observations Macrophage activation syndrome in