An Interleukin‐6–Related Systemic Inflammatory Syndrome in Patients Co‐Infected with Kaposi Sarcoma–Associated Herpesvirus and HIV but without Multicentric Castleman Disease

Abstract

Background Kaposi sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi sarcoma (KS) and multicentric Castleman disease (MCD) in HIV-infected patients. Patients with KSHV-MCD develop fevers, wasting, hypoalbuminemia, cytopenias, and hyponatremia that are related to overproduction of KSHV-encoded vial interleukin (IL)-6 (vIL-6) and human IL-6. Methods We identified 6 HIV-infected patients with KS or serological evidence of KSHV infection who had severe inflammatory MCD-like symptoms but in whom we could not diagnose MCD, and hypothesized that these symptoms resulted from vIL-6 overproduction. Serum vIL-6 levels were assessed in these 6 patients and compared to 8 control patients with symptomatic KSHV-MCD and 32 control patients with KS. KSHV viral load, serum human IL-6 (hIL-6), and human IL-10 were also evaluated. Results Patients with inflammatory MCD-like symptoms but without MCD had elevated vIL-6 levels comparable to patients with symptomatic KSHV-MCD and significantly greater than control patients with KS (P = 0.0026). Elevated hIL-6, IL-10, and KSHV viral loads were also comparable to patients with symptomatic KSHV-MCD and significantly greater than those with KS. Conclusions A subset of patients with HIV and KSHV co-infection, but without MCD, can develop severe systemic inflammatory symptoms associated with elevated levels of KSHV vIL-6, IL-6, and KSHV viral loads. Excess lytic activation of KSHV, production of the lytic gene product vIL6, and associated immunologic dysregulation may underlie the pathophysiology of these symptoms. This IL-6-related inflammatory syndrome is important to consider in critically ill patients with HIV and KSHV co-infection.

High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy

“…KSHV-encoded vIL-6 was measured using a previously described sandwich enzyme-linked immunosorbent assay that used clone v6m 31.2.4 murine monoclonal anti-vIL-6 antibody, 29 and which had been modified from an earlier vIL-6 assay. 13,30,31 The lower limit of detection for serum vIL-6 was 1560 pg/mL and 95% upper limit of reactivity in serum from health blood donors was 2850 pg/mL.…”

“…The assay did not cross-react with hIL-6. 29 In evaluating patients with known KSHV-MCD at different time points, vIL-6 values are presented down to 1560 pg/mL.…”

“…29,32,33 Briefly, DNA was extracted from peripheral blood mononuclear cells (PBMCs) and KSHV DNA was detected using primers for the K6 gene region. 32 The number of cellular equivalents was determined using a quantitative assay for human endogenous retrovirus 3, 34 and KSHV viral load was reported as viral DNA copies per million PBMCs.…”

Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease

“…Untreated, it is usually lethal within 2 to 3 years. 1,7 Patients can develop severe sepsislike manifestations associated with elevated human IL-6, vIL-6, and IL-10, 17 and/or hemophagocytic syndrome. 18,19 Such disease manifestations require urgent treatment.…”

Pulmonary manifestations of human herpesvirus-8 during HIV infection

“…During the lytic phase, numerous genes are expressed and viral homologues of human proinflammatory cytokines, such as viral interleukin 6 (vIL-6), lead to inflammation, angiogenesis and cell growth. Most of the clinical effects of MCD are secondary to viral proteins such as vIL-6 [11][12][13].…”