Alteration of the serum biomarker profiles of visceral leishmaniasis during treatment

Abstract

Until recently, chemotherapy for visceral leishmaniasis (VL; also known as kala-azar) was severely limited by factors such as high cost, route of administration, generation of side effects and potential for resistance. Although largely effective chemotherapies have become available with the introduction of new drugs and multi-drug regimens for VL, these could be further improved by the identification of biomarkers that are altered during effective treatment. The identification of such biomarkers in the circulation would also simplify efficacy trials. In this study we determined immunological signatures within the serum of ethnically and geographically-distinct VL patients (from Bangladesh and Brazil). Our results indicate that inflammatory and regulatory cytokines (IFNγ, TNFα, IL-10, IL-17), as well as levels of growth factors (FGF, VEGF), are elevated within the serum of VL patients from these sites. Examination of samples from Brazilian VL patients during and beyond standard treatment with meglumine antimoniate identified multiple parameters that revert to levels comparable to those of healthy endemic control individuals. The consolidation of these results provides a `response to treatment' signature that could be used within efficacy trials to rapidly and simply determine successful interruption of VL.

Systematic Review of Biomarkers To Monitor Therapeutic Response in Leishmaniasis

“…IFN-␥ levels were found to be significantly elevated in patients with active VL, which was confirmed in a wide range of countries: India (74,75), Bangladesh (70), Brazil (70,72,73,77), Ethiopia (67, 68), Sicily (66), and Iran (65). During and after successful treatment, IFN-␥ levels were found to drop significantly but remained elevated compared to levels in healthy controls (66,70,73,75,78). In contrast, Cenini et al (84) showed that IFN-␥ levels returned to healthy-control levels at the end of treatment.…”

“…The increase of IL-10 concentrations in VL patients was later confirmed in a range of countries, including, among others, India, Brazil, and Ethiopia (65-77). IL-10 levels were found to drop significantly after successful treatment (66,70,73,78) to near-control levels 5 to 7 days posttreatment (74). Ansari et al found no difference in pretreatment IL-10 levels between responsive and unresponsive patients (74).…”

“…Cured mucocutaneous leishmaniasis (MCL) patients demonstrated a higher percentage of IL-10-expressing cells pretreatment than relapsing patients (81). Interestingly, IL-10 was found to be positively correlated with the parasite load in the blood of VL patients (17,70) and lesional tissue of PKDL patients (82).…”

“…Soluble CD40 ligand (sCD40L) (also called sCD154) was significantly decreased in VL patients at diagnosis compared to levels in controls in areas of endemicity (70,87). During treatment, sCD40L levels increased toward healthy control levels.…”

“…Levels of circulating soluble cytokine receptors for IL-2 and IL-4 (sIL-2R and sIL-4R, respectively) were elevated in patients with active VL, with higher concentrations of sIL4R than in patients with other local and systemic parasitic infections (57,(104)(105)(106). Serum sIL-2R concentrations correlated with Leishmania DNA serum levels (70) and significantly decreased during treatment (57,70) but returned to normal only after several months (105). At the start of treatment, sIL-2R levels were also significantly higher in patients developing PKDL than in patients not developing PKDL (64).…”