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 human immunodeficiency virus (HIV)-infected patients. Patients with KSHV-MCD develop fevers, wasting, hypoalbuminemia, cytopenias, and hyponatremia that are related to overproduction of KSHV-encoded viral interleukin (IL)-6 (vIL-6) and human IL-6 (hIL-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 we hypothesized that these symptoms resulted from vIL-6 overproduction. Serum vIL-6 levels were assessed in these 6 patients and compared with levels in 8 control patients with symptomatic KSHV-MCD and 32 control patients with KS. KSHV viral load, serum hIL-6 level, and human IL-10 level were also evaluated.

Results: Patients with inflammatory MCD-like symptoms but without MCD had elevated vIL-6 levels, comparable with levels in patients with symptomatic KSHV-MCD, and had levels that were significantly greater than those in control patients with KS (P = .003). 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.

Conflict of interest statement

Potential Conflicts of Interest.

G.T. is a co-inventor on a patent describing the measurement of KSHV vIL-6. This invention was made when G.T. was an employee of the US Government under 45 Code of Federal Regulations Part 7. All rights, title, and interest to this patent have been assigned to the U.S. Department of Health and Human Services. The government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). R.Y is the spouse of G.T. All other authors: no conflicts.

Figures

Figure 1. Comparisons of Serum vIL-6 between MCD, MCD-like and KS Control Groups

Comparisons of vIL-6 between MCD (n=8) MCD-like (n=6) Severe KS (n= 24) and Mild KS (n=8) groups were performed using Fischer’s exact test (10 transformed pg/ml, p-values are two-sided. ----------- = median - -- - -- - = lower limit of detection.

Figure 2. Comparisons of KSHV Viral Load between MCD, MCD-like and KS Control Groups

Comparisons of PBMC-associated KSHV viral load between MCD (n=8) MCD-like (n=6) Severe KS (n= 22) and Mild KS (n=8) groups were performed using an exact form of the Wilcoxon rank-sum test. Values are log10 transformed copies/106 cells, p- values are two-sided. ----------- = median.

Figure 3. Comparisons of hIL6 between MCD, MCD-like and KS Control Groups

Comparisons of hIL-6 between MCD (n=8) MCD-like (n=6) Severe KS (n= 22) and Mild KS (n=8) groups were performed using an exact form of the Wilcoxon rank-sum test. Values are log10 transformed pg/ml, p-values are two-sided. ----------- = median.

Figure 4. Comparisons of IL-10 between MCD, MCD-like and KS Control Groups

Comparisons of IL-10 between MCD (n=8) MCD-like (n=6) Severe KS (n= 22) and Mild KS (n=8) groups were performed using an exact form of the Wilcoxon rank-sum test. Values are log10 transformed pg/ml, p-values are two-sided. ----------- = median.