Kaposi sarcoma herpes virus (KSHV), also known as human herpesvirus-8 (HHV-8), is a gamma 2 herpesvirus or rhadinovirus. The target cells of KSHV are relatively broad, and include B and T lymphocytes, endothelial cells, and subsets of monocytes and macrophages (¹). It is well-known that KSHV is associated with Kaposi sarcoma (KS), multicentric Castleman disease (MCD; pathologically, the plasma cell variant), and primary effusion lymphoma (¹). KSHV has been detected in 40-50% of HIV-negative patients with MCD, and in nearly all HIV-positive patients with MCD (²). KSHV-positive Castleman disease has its unique histopathologic features owing to the accumulation of virus-infected lymphocytes in the mantle zone, which result in progressive follicular lysis and up-regulation of low affinity nerve growth factor receptor in the stroma around the regressed lymphoid follicles (³). According to recent reports, KSHV is rarely related to the hemophagocytic syndrome, mostly in immunocompromised hosts, such as HIV-positive or transplantation patients (⁴, ⁵). However, KSHV-associated hemophagocytic syndrome has also been described in a HIV-negative, immunocompetent patient with the plasmablastic variant of MCD (plasmablastic microlymphoma) (⁶). Herein, we provide another example of KSHV-associated hemophagocytic syndrome concomitant with KS and Castleman disease of the plasma cell type in a HIV-negative, immunocompetent patient.

Hemophagocytic syndrome is associated with variable systemic diseases, including viral infections, as represented by the Epstein-Barr virus (EBV) (⁷, ⁸). Most of the KSHV-associated hemophagocytic syndromes have been reported in immunocompromised hosts, with few reports in immunocompetent patients (⁶, ⁹). Li et al. (⁶), for the first time, reported a case of KSHV-associated hemophagocytic syndrome in a HIV-negative, immunocompetent host with MCD. Re et al. (⁹) described two additional cases in HIV-negative, non-transplant patients. Our patient had no history suggesting immune deficiency before the diagnosis of Castleman disease. Although he had diabetes mellitus, it was detected only three months previously and had been well controlled by oral hypoglycemic agents. It is improbable that the short-term administration of prednisolone for the management of Castleman disease resulted in severe immunosuppression. The major clinicopathologic features of the reported and present cases with KSHV-associated hemophagocytic syndrome in immunocompetent patients are summarized in Table 1. Notably, all four of the patients followed a rapid and fatal clinical course, and two of the patients also had MCD. All of them appeared in old age. The concurrence of KS and Castleman disease of the plasma cell type in this case further demonstrates that the hemophagocytic syndrome could occur as a fatal complication of KSHV-related disease, even in HIV-negative and non-transplant immunocompetent hosts. KSHV-associated hemophagocytic syndrome has been reported to co-occur with KSHV infection related diseases such as Kaposi sarcoma, multicentric Castleman disease or plasma effusion lymphoma in immunocompromised host. This is the first case of multiple KSHV associated diseases including MDC and KS with KSHV-associated hemophagocytic syndrome in an HIV-negative, non-transplant, immunocompetent patient. We thought that our patients died of DIC and renal failure complicated by severe hemophagocytic syndrome.

In the pathogenesis of the hemophagocytic syndrome, many cytokines, including IFN-?, IL-6, IL-10, and IL-12, are known to be important (⁷). In the case of KHSV-related hemophagocytic syndrome, direct infection of monocytes by KSHV or a paracrine influence from virus reactivation in reservoir cells has been suggested as a possible pathogenetic mechanism (⁴). Li et al. (⁶) speculated that proliferation of KSHV-infected plasmablasts might have resulted in a cytokine storm, leading to virus-associated hemophagocytic syndrome similar to EBV-associated T cell lymphoproliferative disorder.

IL-6 is known as a key cytokine involved in the pathogenesis of KSHV-associated diseases (⁷). IL-6 is a multipotent cytokine having multiple biologic activities, including promotion of B cell proliferation and differentiation with plasmacytosis, stimulation of inflammatory pathways, and induction of B cell malignancies (¹⁰). KSHV encodes a viral homologue of IL-6 (vIL-6), which can functionally mimic human IL-6 and also induce the production of human IL-6 (¹⁰). In a murine model, deregulated expression of IL-6 brought about MCD-like features, including splenomegaly, extensive plasma cell infiltration of the lymphoreticular system, and polyclonal hypergammaglobulinemia (¹¹). Patients with Castleman disease of the plasma cell type have elevated serum IL-6 levels (¹²). vIL-6 also induces vascular endothelial growth factor (VEGF), and induces local tissue damage and attracted inflammatory cells (¹³, ¹⁴). Thalidomide, a powerful anticytokine effector, has been used for resolution of the systemic manifestations of MCD (¹⁰). Recently, humanized anti-IL-6 receptor antibody (tocilizumab) has proven to be useful for the treatment of MCD (¹⁵). Although IL-6 was not evaluated in our case, the presence of abundant plasmacytoid or plasma cells in the lymph nodes and spleen, and T cell proliferation in the bone marrow, suggest that IL-6 might play an important role in disease progression and the hemophagocytic syndrome. Therefore, the present case emphasizes the consideration of anti-IL-6 therapy for the management of potentially fatal complication including hemophagocytic syndrome in MCD patients.

This work was partly supported by the Korean Science & Engineering Foundation (KOSEF) through the Tumor Immunity Medical Research Center at Seoul National University College of Medicine.