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.

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Key Points Human IL-6 and a viral IL-6 homolog encoded by KSHV/HHV8 can independently or together lead to flares of KSHV-associated MCD. KSHV-MCD disease flares were more severe where both human and viral IL-6 were elevated, suggesting they jointly contribute to severity.

Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.