Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome

Abstract

Soon after the discovery of Kaposi sarcoma (KS)-associated herpesvirus (KSHV), it was appreciated that this virus was associated with most cases of multicentric Castleman disease (MCD) arising in patients infected with human immunodeficiency virus. It has subsequently been recognized that KSHV-MCD is a distinct entity from other forms of MCD. Like MCD that is unrelated to KSHV, the clinical presentation of KSHV-MCD is dominated by systemic inflammatory symptoms including fevers, cachexia, and laboratory abnormalities including cytopenias, hypoalbuminemia, hyponatremia, and elevated C-reactive protein. Pathologically KSHV-MCD is characterized by polyclonal, IgM-lambda restricted plasmacytoid cells in the intrafollicular areas of affected lymph nodes. A portion of these cells are infected with KSHV and a sizable subset of these cells express KSHV lytic genes including a viral homolog of interleukin-6 (vIL-6). Patients with KSHV-MCD generally have elevated KSHV viral loads in their peripheral blood. Production of vIL-6 and induction of human (h) IL-6 both contribute to symptoms, perhaps in combination with overproduction of IL-10 and other cytokines. Until recently, the prognosis of patients with KSHV-MCD was poor. Recent therapeutic advances targeting KSHV-infected B cells with the anti-CD20 monoclonal antibody rituximab and utilizing KSHV enzymes to target KSHV-infected cells have substantially improved patient outcomes. Recently another KSHV-associated condition, the KSHV inflammatory cytokine syndrome (KICS) has been described. Its clinical manifestations resemble those of KSHV-MCD but lymphadenopathy is not prominent and the pathologic nodal changes of KSHV-MCD are absent. Patients with KICS exhibit elevated KSHV viral loads and elevation of vIL-6, homolog of human interleukin-6 and IL-10 comparable to those seen in KSHV-MCD; the cellular origin of these is a matter of investigation. KICS may contribute to the inflammatory symptoms seen in some patients with severe KS or primary effusion lymphoma. Additional research is needed to better define the clinical spectrum of KICS and its relationship to KSHV-MCD. In additional, research is needed to better understand the pathogenesis and epidemiology of both KICS and KSHV-MCD, as well as the optimal therapy for both of these disorders.

Keywords: KSHV inflammatory cytokine syndrome; Kaposi sarcoma-associated herpesvirus; human herpesvirus 8; human immunodeficiency virus; interleukin-6; multicentric Castleman disease.

Figure 1

Lymph Node from a Patient with KSHV–MCD Stained for vIL-6. Germinal center of a lymph node from a patient with KSHV–MCD, stained with a monoclonal antibody to vIL-6 and an alkaline phosphatase substrate. Cells expressing vIL-6 stain in blue; these cells are located primarily in the mantle region around the germinal center. The tissue was studied under a protocol approved by the Institutional Review Board of the National Cancer Institute, and the patient gave written informed consent.

Figure 2

Viral and cytokine elevations in patients with KICS, KSHV–MCD, and KS. Statistically significant differences in KSHV viral load, viral, and human cytokines were seen in KICS patients compared with controls with KS alone, at levels comparable to those seen in KSHV–MCD. Horizontal lines indicate median value, and the dashed line indicates the lower limit of detection. Values are log transformed; viral and human IL-6 and IL-10 are picograms per milliliter; KSHV VL is copies/10⁶ cells. Note that several of the patients with severe KS and elevated vIL-6 had laboratory abnormalities suggestive of KICS, but did not meet the operative case definition for this series. Modified from Uldrick et al. (2010a), with permission.