Abstract
BackgroundSleeping 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.MethodsA 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.ResultsMedian 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%).ConclusionOur 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.
Highlights
Human African Trypanosomiasis (HAT) or sleeping sickness is caused by extra-cellular protozoan parasites T. b. rhodesiense (East and Southern Africa) and T. b. gambiense (West and central Africa)
When early stage and late stage cerebrospinal fluid (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
Interleukin (IL)-6 and IL-10 in Sleeping Sickness 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 central nervous system (CNS) infections, our findings should be further validated in a large cohort of patients including those with other inflammatory diseases such as cerebral malaria
Summary
Human African Trypanosomiasis (HAT) or sleeping sickness is caused by extra-cellular protozoan parasites T. b. rhodesiense (East and Southern Africa) and T. b. gambiense (West and central Africa). A wide spectrum of clinical presentations coupled with differences in disease progression and severity has been observed [3,4]. The late stage of the disease has been associated with elevated levels of counter inflammatory cytokines in the CNS of both HAT patients and experimental animal models [7]. The few previous studies indicated that IL-10 and IL-6 were up regulated in the late stage and were associated with reduced severity of neuropathology in experimental [10] and natural infections [3,12,13]. 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. We hypothesized that disease progression and severity of the neurological response is modulated by cytokines
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