Post kala-azar dermal leishmaniasis in the Indian sub-continent: challenges and strategies for elimination

Abstract

Visceral leishmaniasis (VL) is a severe and often fatal form of leishmaniasis caused by Leishmania donovani in the Indian sub-continent. Post Kala-azar Dermal Leishmaniasis (PKDL) is a late cutaneous manifestation of VL, typically occurring after apparent cure of VL, but sometimes even without a prior history of VL in India. PKDL serves as a significant yet neglected reservoir of infection and plays a crucial role in the transmission of the disease, posing a serious threat to the VL elimination program in the Indian sub-continent. Therefore, the eradication of PKDL should be a priority within the current VL elimination program aimed at achieving a goal of less than 1 case per 10,000 in the population at the district or sub-district levels of VL endemic areas. To accomplish this, a comprehensive understanding of the pathogenesis of PKDL is essential, as well as developing strategies for disease management. This review provides an overview of the current status of diagnosis and treatment options for PKDL, highlighting our current knowledge of the immune responses underlying disease development and progression. Additionally, the review discusses the impact of PKDL on elimination programs and propose strategies to overcome this challenge and achieve the goal of elimination. By addressing the diagnostic and therapeutic gaps, optimizing surveillance and control measures, and implementing effective intervention strategies, it is possible to mitigate the burden of PKDL and facilitate the successful elimination of VL in the Indian sub-continent.

Keywords: IL-10; elimination; immune regulation; intervention strategies; post kala-azar dermal leishmaniasis; visceral leishmaniasis.

Figure 1

Potential interplay between environmental factors and host factors that can contribute to the conversion of VL into PKDL. UV-B radiation causes alterations in the morphology of epidermal Langerhans cells (E-LC cells) leading to suppressed expression of MHC-II and co-stimulatory molecules, but enhances the level of IL-10 (1). IL-4 secreted by Th2 cells activates dermal dendritic cells (dDCs) (2) which contribute to the cytokine pool by producing more IL-10, which creates an immunosuppressive environment and promote the expansion of regulatory T (Treg) cells (3), which further aids in parasite persistence (4). Activated macrophages secrete TGF-β, which can activate Treg cells and promote increased secretion of TGF-β, contributing to parasite persistence (5). Inadequate treatment of VL with anti-leishmanial drugs can result in the development of PKDL (6). Failure of organ-specific T cell memory response: Self-healing patients in Sudan show an increased level of effector memory T cells, indicating an enhanced immune response in the skin while PKDL patients in the Indian subcontinent have a lower titer of effector memory T cells, leading to a weak immune response and non-healing nature of the disease (7). T- cells secrete both IFN-γ and IL-10 (8) and in individuals with polymorphism in IFN-γ receptor, failure of appropriate IFN-γ signaling leads to immune suppression and dominance of IL-10 (9) while Individuals with high IFN-γR expression are least prone to developing PKDL (10).

Figure 2

Strategies to prevent disease transmission. While the role of VL in disease transmission is well established, the contributions of PKDL and asymptomatic cases in transmission are still not fully understood (1). The presence of asymptomatic and PKDL cases can increase the vulnerability of the population to the disease (2). Therefore, employing transmission-blocking strategies such as drugs, IRS, and ITNs can be effective in preventing disease transmission and reducing population susceptibility (3). [VL-Visceral leishmania, PKDL-Post kala-azar dermal leishmaniasis, IRS-Indoor residual spraying, ITNs-Insecticide-treated nets].