Interleukin (IL)-6 and IL-10 Are Up Regulated in Late Stage Trypanosoma brucei rhodesiense Sleeping Sickness.

Background: Sleeping sickness due to Trypanosoma brucei rhodesiense has a wide spectrum of clinical presentations coupled with differences in disease progression and severity across East and Southern Africa. The disease progresses from an early (hemo-lymphatic) stage to the late (meningoencephalitic) stage characterized by presence of parasites in the central nervous system. We hypothesized that disease progression and severity of the neurological response is modulated by cytokines. Methods: A total of 55 sleeping sickness cases and 41 healthy controls were recruited passively at Lwala hospital, in Northern Uganda. A panel of six cytokines (IFN-γ, IL1-β, TNF-α, IL-6, TGF-β and IL-10) were assayed from paired plasma and cerebrospinal fluid (CSF) samples. Cytokine concentrations were analyzed in relation to disease progression, clinical presentation and severity of neurological responses. Results: Median plasma levels (pg/ml) of IFN-γ (46.3), IL-6 (61.7), TGF-β (8755) and IL-10 (256.6) were significantly higher in cases compared to controls (p< 0.0001). When early stage and late stage CSF cytokines were compared, IL-10 and IL-6 were up regulated in late stage patients and were associated with a reduction in tremors and cranioneuropathy. IL-10 had a higher staging accuracy with a sensitivity of 85.7% (95% CI, 63.7%-97%) and a specificity of 100% (95% CI, 39.8%-100%) while for IL-6, a specificity of 100% (95% CI, 47.8%-100%) gave a sensitivity of 83.3% (95% CI, 62.2%-95.3%). Conclusion: Our study demonstrates the role of host inflammatory cytokines in modulating the progression and severity of neurological responses in sleeping sickness. We demonstrate here an up-regulation of IL-6 and IL-10 during the late stage with a potential as adjunct stage biomarkers. Given that both cytokines could potentially be elevated by other CNS infections, our findings should be further validated in a large cohort of patients including those with other inflammatory diseases such as cerebral malaria. Author Summary: Sleeping sickness in east and central Africa is caused by a protozoan parasite, Trypanosoma brucei rhodesiense. About 12.3 million people are at a risk of acquiring the disease that is fatal if untreated. The disease progresses from an early stage with trypanosomes in blood and lymph to a late stage in which trypanosomes enter the central nervous system. Variations in disease presentation, progression and severity of the disease have been reported and cytokines have been proposed as potential players. Before treatment is commenced, disease stage has to be ascertained since treatment for the two stages is different. The currently used staging criteria depends on finding trypanosomes in the cerebrospinal fluids (CSF) and elevation in CSF white blood cells however, this has been found to have low sensitivity. We therefore measured plasma and cerebrospinal fluid cytokine concentrations and determined associations with disease presentation, stage progression and severity of the neurological response. Our study shows that concentrations of specific cytokines are elevated in sleeping sickness patients and have a potential to discriminate between patients in early or late stage of infection. [ABSTRACT FROM AUTHOR]