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.

Kaposi Sarcoma-associated Herpesvirus: mechanisms of oncogenesis

“…A related syndrome, called KSHV inflammatory cytokine syndrome (KICS), has also been described. These patients do not have lymphadenopathies typically associated with MCD, but have a similar cytokine storm, including detection of vIL6 in patient's serum, and elevated IL6 and IL10 [77,78]. …”

KSHV

“…Interestingly, KSHV infection in MCD is quite lytic as compared to KS and PEL (Chadburn et al, 2008; Polizzotto, Uldrick, Hu, & Yarchoan, 2012). KSHV is detected in less than 40% of HIV-negative MCD cases (Nishimoto et al, 2005; Parravicini et al, 1997; Soulier et al, 1995; Waterston & Bower, 2004); however, in patients coinfected with HIV and KSHV, MCD tends to be very aggressive with rapid disease progression.…”

Thoracic Diseases Associated with HIV Infection in the Era of Antiretroviral Therapy: Clinical and Imaging Findings

“…A high level of plasma HHV-8 DNA was detected. (47). This syndrome shares many of the features of MCD but is different pathologically.…”

“…Ultimately, tissue or lymph node biopsy fails to demonstrate MCD. The differential diagnosis includes MCD and sepsis, and therefore tissue or lymph node biopsy is required (47).…”