Clinical Features and Outcomes of Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-associated Inflammation: Prospective Characterization of KSHV Inflammatory Cytokine Syndrome (KICS)

Abstract

Background: Kaposi sarcoma herpesvirus (KSHV) is the cause of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and a form of Castleman disease (KSHV-MCD). Recently a KSHV-associated inflammatory cytokine syndrome (KICS) distinct from KSHV-MCD was reported.

Methods: We prospectively characterized the clinical, laboratory, virologic and immunologic features of KICS by evaluating symptomatic adults with KSHV using a prespecified definition. These features and overall survival were compared with controls from 2 prospectively characterized human immunodeficiency virus (HIV)-infected cohorts, including 1 with KSHV coinfection.

Results: All 10 KICS subjects were HIV infected males; 5 had HIV viral load (VL) suppressed <50 copies mL (median 72, range <50-74 375); all had KS and 2 also had PEL. All had multiple severe symptoms attributable to KICS: median number of symptoms 8 (6-11), median grade of worst symptom 3 (2-4). These included gastrointestinal disturbance (present in 9); edema (9); respiratory (6); and effusions (5). Laboratory abnormalities included anemia (all); hypoalbuminemia (all) and thrombocytopenia (6). None developed KSHV-MCD; 6 died with median survival from KICS diagnosis 13.6 months. KICS subjects compared with controls had more severe symptoms; lower hemoglobin and albumin; higher C-reactive protein; higher KSHV VL; elevated interleukin (IL)-6 and IL-10; and an increased risk of death (all P < .05). Anemia and hypoalbuminemia at presentation were independently associated with early death.

Conclusions: KICS subjects demonstrated diverse severe symptoms, a high rate of KSHV-associated tumors, high mortality, and a distinct IL-6/IL-10 signature. KICS may be an important unrecognized cause of morbidity and mortality, including symptoms previously ascribed to HIV. Exploration of KSHV-directed therapy is warranted.

Keywords: HIV; Human Herpesvirus 8 (HHV-8); IL-10; IL-6; Kaposi sarcoma herpesvirus (KSHV).

Figure 1.

Clinical manifestations and clinical course of a representative patient with Kaposi sarcoma herpesvirus (KSHV)-associated inflammatory cytokine syndrome (KICS). Note: Functional and structural imaging, histopathology, and laboratory abnormalities of a representative subject are illustrated. Presenting symptoms included respiratory failure, gastrointestinal symptoms, and generalized hemorrhage in the setting of thrombocytopenia. Kaposi sarcoma (KS) was present with limited cutaneous involvement (B) but severe pulmonary involvement shown in bronchoscopy and computed tomography (C) together with hepatic and lymph node involvement demonstrated by histopathology (D). There were bilateral pleural effusions (C), ascites, and severe soft tissue edema. ¹⁸F-fluoro deoxyglucose positron emission tomography with computed tomography (¹⁸FDG-PET) (A) demonstrated tracer uptake at sites of KS, including limited lymph nodes, without adenopathy or splenomegaly. Laboratory abnormalities (E) included markedly elevated C-reactive protein (CRP), severe thrombocytopenia, severe hypoalbuminemia and anemia. KSHV viral load (VL) in PBMCs at presentation was 20 250 copies/10⁶ peripheral blood mononuclear cells (PBMCs) and in plasma 3.99 × 10⁶ copies/mL. There was no evidence of intercurrent infection, no evidence of KSHV-MCD on lymph node biopsy (D) and no evidence of primary effusion lymphoma. The patient was treated with liposomal doxorubicin and antiretroviral therapy together intravenous immunoglobulin and a single dose of rituximab and made a gradual improvement (E) before succumbing to a pulmonary complication. Abbreviation: MCD, multicentric Castleman disease.

Figure 2.

Systemic inflammation, Kaposi sarcoma herpesvirus (KSHV) activation and human interleukin (IL)-6 and IL-10 elevation in patients with KSHV-associated inflammatory cytokine syndrome (KICS) compared with controls. Note: Systemic inflammation measured by C-reactive protein (CRP), KSHV replication measured by viral load (VL) in peripheral blood mononuclear cells (PBMCs), and circulating IL-6 and IL-10 were each markedly elevated in KICS subjects compared with each of the 4 control groups, including the 2 groups with uncontrolled human immunodeficiency virus (HIV) viremia. P values are by Wilcoxon rank sum test for comparison to KICS patients. Note: all values are log transformed.

Figure 3.

Overall survival in Kaposi sarcoma herpesvirus-associated inflammatory cytokine syndrome (KICS) subjects compared with controls. Note: Survival was significantly worse among KICS subjects than controls (P < .0001). Note that the 4 control cohorts are grouped here for the purposes of analysis, as only 1 death occurred among all 40 patients in those 4 groups. Abbreviation: HIV, human immunodeficiency virus.