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.

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 (<2850 vs. ≥ 2850 pg/ml). Values shown are log₁₀ 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.