The successful treatment of haemophagocytic syndrome in patients with human immunodeficiency virus-associated multi-centric Castleman’s disease J. Stebbing,* † S. Ngan, † H. Ibrahim, † P. Charles, ‡ M. Nelson, § P. Kelleher, ¶ K. N. Naresh** and M. Bower † Departments of *Oncology, ‡ Academic Biochemistry and **Histopathology, Imperial College School of Medicine, Imperial College Healthcare NHS Trust, London, UK, Departments of † Oncology and ¶ Immunology, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, UK, and § Department of HIV Medicine, Chelsea and Westminster Hospital, London, UK Summary Both virus-associated haemophagocytic syndrome (HPS) and human immu- nodeficiency virus-associated multi-centric Castleman’s disease (HIV-MCD) induced by human herpesvirus-8 (HHV-8) are extremely rare. We therefore wished to investigate their occurrence together, and establish the degree of cytokine activation present. From a prospective cohort of individuals with HIV-MCD, we investigated the incidence and outcomes of HPS and measured 15 inflammatory cytokines and the plasma HHV-8 viral loads before and during follow-up. Of 44 patients with HIV-MCD with an incidence of 4·3/10 000 patient years, four individuals (9%) were diagnosed with HPS. All are in remission (range 6–28 months) following splenectomy, etoposide and rituximab-based therapy. Plasma HHV-8 levels were raised markedly at pre- sentation (median 3 840 000 copies/ml). Histological samples from spleen, splenic hilar lymph nodes and bone marrow demonstrated increased phago- cytosis by histiocytes and presence of HHV-8-infected plasmablasts outside the follicles. Surprisingly, many known inflammatory plasma cytokines were not elevated, although interleukin (IL)-8 and interferon-g were increased in all cases and IL-6 levels were raised in three of four patients. HPS in the setting of HIV-MCD is common and treatment can be successful provided the diagnosis is made appropriately. Systemic activation of cytokines was limited, suggest- ing that immunosuppressive therapy with steroids is not indicated in HHV- 8-driven HPS. Keywords: cytokines, haemophagocytic syndrome, human herpesvirus-8, multi-centric Castleman’s disease Accepted for publication 1 September 2008 Correspondence: Dr J. Stebbing and Professor M. Bower, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, UK. E-mail: j.stebbing@imperial.ac.uk and m.bower@imperial.ac.uk Introduction Haemophagocytic syndrome (HPS) is a reactive disorder of the reticulo-endothelial system characterized by histiocyte proliferation associated with uncontrolled activation of natural killer, CD4-positive T regulatory and CD8-positive cytotoxic T cells, leading to multi-organ failure when untreated [1]. First described in 1939 in a patient with sickle cell anaemia [2], this rare condition can be divided into primary or hereditary HPS and secondary or reactive HPS, the latter occurring in the setting of malignancies, autoimmune disease and/or infections [3–5]. Virus- associated secondary HPS has additional features more frequently, such as high fever, constitutional symptoms, liver dysfunction, coagulation abnormalities, peripheral blood cytopenias, hepatosplenomegaly and lymphadenopa- thy [3–5]. Clinically, patients with virus-associated secondary HPS present with similar sign and symptoms to multi-centric Castleman’s disease (MCD)[6]. In addition, both have been related aetiologically to infection with the g-herpesviridae, Epstein–Barr virus (EBV) and human herpesvirus-8 (HHV-8) (also known as Kaposi’s sarcoma-associated herp- esvirus, KSHV) [7–9]. While diagnostic criteria from the Histiocyte Society are well established [10,11], clinicians should be aware of HPS in individuals with fever, cytopenias, organomegaly and persistent g-herpesvirus infection; early diagnosis and intervention are required. We describe HPS in the setting of human immuno- deficiency virus (HIV)-MCD, the largest case series in this setting to the best of our knowledge [8,12,13]. In addition, patients’ cytokine and HHV-8 profiles were measured; sur- prisingly, a uniformly raised pattern of known inflammatory cytokines was not observed. Clinical and Experimental Immunology ORIGINAL ARTICLE doi:10.1111/j.1365-2249.2008.03786.x 399 © 2008 British Society for Immunology, Clinical and Experimental Immunology, 154: 399–405