Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis.

Cutaneous leishmaniasis (CL) is caused by Leishmania donovani in Sri Lanka. Pentavalent antimonials (e.g., sodium stibogluconate [SSG]) remain first-line drugs for CL with no new effective treatments emerging. We studied whole blood and lesion transcriptomes from Sri Lankan patients with CL at presentation and during SSG treatment. From lesions but not whole blood, we identified differential expression of immune-related genes, including immune checkpoint molecules, after onset of treatment. Using spatial profiling and RNA-FISH, we confirmed reduced expression of programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) proteins on treatment in lesions of a second validation cohort and further demonstrated significantly higher expression of these checkpoint molecules on parasite-infected compared with noninfected lesional CD68+ monocytes and macrophages. Crucially, early reduction in PD-L1 but not IDO1 expression was predictive of rate of clinical cure (HR = 4.88) and occurred in parallel with reduction in parasite load. Our data support a model whereby the initial anti-leishmanial activity of antimonial drugs alleviates checkpoint inhibition on T cells, facilitating immune-drug synergism and clinical cure. Our findings demonstrate that PD-L1 expression can be used as a predictor of rapidity of clinical response to SSG treatment in Sri Lanka and support further evaluation of PD-L1 as a host-directed therapeutic in leishmaniasis.

Randomized, double-blind study on intralesional metronidazole versus intralesional sodium stibogluconate in Leishmania donovani cutaneous leishmaniasis.

OBJECTIVES: The aim of our study was to assess the efficacy of intralesional metronidazole on Leishmania donovani cutaneous leishmaniasis (CL). MATERIAL AND METHODS: A total of 188 patients with CL were randomly allocated to intralesional sodium stibogluconate (SSG) and intralesional metronidazole. Cure was assessed after 1-10 injections. Cure rates were assessed for statistical significance using chi-square test at p = .05 level (SLCTR/2014/028). RESULTS: When the treatment cutoff was taken at 100%, the rate of cure for SSG (n = 64, 65.6%) was higher than that of metronidazole (n = 45, 48.9%): statistically significant at p < .05 level (Yates corrected chi-square 5.37, df = 1, p < .5). When the treatment cutoff was taken at >80%, the rate of cure for SSG (n = 75, 77.1%) was also higher than that of metronidazole (n = 58, 63.0%): statistically significant at p < .05 level (Yates corrected chi-square 4.46, df = 1, p < .5). Since it is based on a smaller sample, we estimated the statistical power of the test at a cutoff of 100% [above 80%] results identified a risk ratio of 1.4 [1.3], and a statistical power based on normal approximation at 74.8% [70.0%], respectively. CONCLUSION: This study showed that intralesional SSG has the best response against CL, while intralesional metronidazole was an effective alternative treatment.

Efficacy of a new rapid diagnostic test kit to diagnose Sri Lankan cutaneous leishmaniasis caused by Leishmania donovani.

BACKGROUND: Cutaneous leishmaniasis (CL) in Sri Lanka is caused by Leishmania donovani. This study assessed the diagnostic value of a new rapid diagnostic immunochromatographic strip (CL-Detect™ IC-RDT), that captures the peroxidoxin antigen of Leishmania amastigotes. METHODOLOGY/PRINCIPAL FINDINGS: We sampled 74 clinically suspected CL lesions, of which 59 (79.7%) were positive by PCR, 43 (58.1%) by Giemsa stained slit skin smear (SSS) and 21 (28.4%) by the new IC-RDT. All samples which were positive either by SSS or IC-RDT or both were positive by PCR. The sensitivities of the IC-RDT and SSS compared to PCR were 36% and 73%, respectively. Fifteen patients from this endemic region were negative by all three tests. Twenty two clinically non-CL skin lesions from a CL non-endemic region were also negative by all three methods. Specificity and PPV of both IC-RDT and SSS compared to PCR were 100%; the NPVs of IC-RDT and SSS were 37% and 58%, respectively. The median parasite grading of the 59 PCR positive samples was 2+ (1-10 parasites/100 HPFs) and IC-RDT positive lesions was 3+ (1-10 parasites /10HPFs). The duration of the lesion was not associated with IC-RDT positivity. CONCLUSIONS/SIGNIFICANCE: The median parasite grade of Sri Lankan CL lesions is low. The low sensitivities of SSS and CL Detect™ IC-RDT may be due to low parasite counts or low expression of peroxidoxin antigen in amastigotes of the Sri Lankan L. donovani strain. Our results indicate that negative SSS has to be combined with PCR for confirmation of CL in Sri Lanka. The current commercially available IC-RDT is not suitable to diagnose CL in Sri Lanka; an IC-RDT with improved sensitivity to detect L. donovani would be a valuable addition in the diagnostic tool kit for Sri Lanka.