Cutaneous leishmaniasis

doi:10.1016/j.clindermatol.2006.05.008

Clinics in Dermatology

Volume 25, Issue 2, March–April 2007, Pages 203-211

https://doi.org/10.1016/j.clindermatol.2006.05.008 Get rights and content

Abstract

Cutaneous leishmaniasis is a widespread tropical infection caused by numerous different species of Leishmania protozoa that are transmitted by sandflies. Its clinical presentations are extremely diverse and dependent on a variety of parasite and host factors that are poorly understood. Diagnosis should aim to identify the exact species involved, but this requires laboratory investigations that are not widely available. No single ideal treatment has been identified, and those available are limited by variable success rates and toxicity. Clinical guidelines are needed to make better use of the investigations and treatments that do exist. Prevention is currently limited to bite prevention measures.

Introduction

Leishmaniasis is an infection caused by various species of Leishmania protozoa, which are usually transmitted by the bite of various species of phlebotomine sandflies. It occurs as a spectrum of clinical syndromes, which are usually divided into cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and visceral leishmaniasis (VL). The epidemiology and clinical features of the disease are highly variable due to the interplay of numerous factors in the parasites, vectors, hosts and environments involved. Laboratory diagnosis of cases can be difficult, especially when resources are limited or species identification is required. Good therapeutic trials require laboratory confirmation of cases, but this may reduce the numbers enrolled and result in trials that are underpowered. Different therapies have different efficacies against different Leishmania spp, and some are associated with significant toxicity. Hence, the optimum management of CL remains a specialist concern.

Section snippets

Epidemiology

Leishmaniasis is endemic in 88 countries throughout Latin America, Africa, Asia, and southern Europe (Fig. 1). Approximately 350 million people are thought to be at risk, with a worldwide prevalence of 12 million and an annual incidence of 1.5 million cases of CL. These figures are expected to rise because of global warming and changes in human ecology.¹ Epidemics may occur when large numbers of nonimmune humans become exposed to infection for the first time, which may occur because of their

Etiology

There are 14 species of Leishmania that commonly cause human leishmaniasis, and the relationships between different species and clinical syndromes are usually simplified as shown in Table 1. For clinical reasons, it is important to differentiate New World species of the L (Leishmania) sub-genus (L mexicana complex) from those of the (L Viannia) sub-genus (L braziliensis complex); because species of the latter are associated with more severe and prolonged disease and also the risk of MCL

Pathology

The Leishmania life cycle begins when parasites in their promastigote form are inoculated by a sandfly bite into the skin of a mammalian host. Tissue macrophages phagocytose these Leishmania organisms, which turn into their amastigote form many will survive within the macrophages because of a variety of sophisticated defense mechanisms. The Leishmania parasites then multiply and spread to other macrophages dependent on various parasite and host factors. In CL, the infection is usually limited

Clinical features

Patients may not recall the initial sandfly bite that leads to CL, and so, a lack of reported bites should not be used to exclude the diagnosis. Incubation periods can vary from a few days to many months, and skin lesions may initially be ignored or misdiagnosed.

Acute CL usually presents as a small papule that enlarges and ulcerates at its center to produce a volcano-shaped “wet” lesion (Fig. 2). Ulcerated lesions are typical of infection due to Leishmania major and the New World species.

Differential diagnosis

Cutaneous leishmaniasis has a broad differential diagnosis because of its diverse clinical presentations.³⁸ Most cases will present with a nonhealing skin ulcer, which is initially thought to be an infected insect bite or a true “tropical ulcer.” Less common bacterial causes include actinomycetoma, Buruli ulcer, ulceroglandular tularemia, and cutaneous anthrax, but these can usually be distinguished by their clinical features. Cutaneous tuberculosis, however, produces a variety of lesions and

Investigations

A clinical diagnosis of CL may be possible in endemic areas or where there is an obvious travel history. Laboratory confirmation, however, should be sought wherever possible because of the broad differential diagnosis and potentially toxic treatments that may be required. The investigations available have a wide range of reported sensitivities because of variations in the techniques used and because results are usually worse for older lesions. Good sampling technique39, 40 and close liaison

Treatment

The large number of reported treatments for CL indicates that no single ideal therapy has yet been identified. When reviewing therapeutic trials, it is important to note the natural history of the disease, the quality of trials with respect to the identification of parasites and significance of results, and also whether the reported findings are comparable with other trials or applicable in different settings.

With so many treatments available against CL, it is also not surprising that

Prevention

There is currently no chemoprophylaxis or immunoprophylaxis (vaccination) available to protect against CL, although prospects for a vaccine remain high.22, 80 Primary prevention relies on managed control of the maintenance host(s) and sandfly bite prevention measures. Although individual measures may not produce statistically significant protection, it is likely that a combination of measures will produce a cumulative protective effect.⁸¹ Secondary and tertiary prevention are dependent on the

Summary

Cutaneous leishmaniasis is now recognized as a complex and highly variable disease in terms of its epidemiology, etiology, pathology, and clinical features. Scientific advances have led to significant improvements in laboratory diagnosis, but currently available treatments are unsatisfactory. The development of better therapies and vaccines represent major challenges for the future.

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Expression analysis of DHFR and PTR1 genes in Leishmania major expose to olive leaf extract
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Among neglected tropical diseases (NTD) following malaria, leishmaniosis has claimed the largest mortality rate (Georgiadou, Makaritsis, and Dalekos 2015). None of the current anti-leishmanial drugs can be considered ideal (Minodier and Parola 2007; Mohapatra 2014). The dihydrofolate reductase- thymidylate synthase (DHFR-TS) leads to DNA synthesis in the parasite and its inhibition causes the death of the parasite. Meanwhile, pteridine reductase1 (PTR1) enzyme, because of having a similar role to DHFR in the parasite, causes by-pass of DHFR enzyme inhibition thereby resulting an incidence of drug resistance in the parasite (Nare et al. 1997b). Considering the current problems regarding leishmaniosis treatment, developing new drugs with less toxicity and greater efficacy plus lower costs has changed into a necessity. The present study examined the effect of olive leaf extract (OLE) at concentrations 6.25, 12.5, 25, 50, and 100 µg/ml on the expression of DHFR and PTR1 genes in Leishmania major parasite. The parasite samples were incubated in RPMI₁₆₄₀ culture medium in the presence of five mentioned concentrations of OLE. A quantitative real-time PCR technique was used to analyze the DHFR and PTR1 gene expressions. The results revealed that the expression of DHFR gene at 6.25 µg/ml extract increased significantly (p<0.05), while it diminished significantly at 25 µg/ml. At other studied concentrations, DHFR gene showed underexpression compared to the control group, which was not statistically significant (p>0.05). The expression of PTR1 gene at concentrations 6.25, 50, and 100 µg/ml of the olive leaf extract increased significantly (p<0.05). The expression of PTR1 gene at 12.5 µg/ml concentration decreased compared to the control group, while it increased at 25 µg/ml, though the changes in the gene expression at these two concentrations were not statistically significant (p>0.05). The findings of the present study suggest that OLE can reduce DHFR expression, but its effect of reducing PTR1 expression was not very notable, with its influence being greater on DHFR underexpression rather than PTR1.
Statistical optimization of co-loaded rifampicin and pentamidine polymeric nanoparticles for the treatment of cutaneous leishmaniasis
2023, Journal of Drug Delivery Science and Technology
Topical drug delivery against cutaneous leishmaniasis (CL) serves as an effective alternate approach to improve efficacy and reduce systemic adverse effects. The purpose of this study was to develop and investigate the potential of rifampicin and pentamidine co-loaded polymeric nanoparticles (RIF-PTM-PNP) for targeting the Leishmania infected macrophages and its effective antileishmanial therapy. RIF-PTM-PNP were prepared by modified ionic gelation method, trailed by their incorporation into 1% Carbopol gel to prepare RIF-PTM-PNP-Gel. The gel was formulated to ensure the retention of PNP on skin for extended period of time. Formulations were statistically optimized via Box-Behnken design (BBD) based on their particle size (P.S), zeta potential (Z.P) and percent entrapment efficiency (%EE). The optimized RIF-PTM-PNP formulation was further assessed for surface morphology and components compatibility via transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR), respectively. Similarly, RIF-PTM-PNP-Gel was evaluated for physiochemical and rheological attributes. In-vitro drug release profile of RIF-PTM-PNP was determined and compared with RIF-Solution, PTM-Solution and RIF-PTM-PNP-Gel. Moreover, ex-vivo permeation analysis of all the test groups were performed to check their permeation profiles. The in-vitro antileishmanial assay, ex-vivo cell uptake, cell viability and cell toxicity studies of the developed formulations were also accomplished. The optimized formulation indicated suitable particle properties including, 163.1 nm P.S, 0.296 PDI, +29.7 mV Z.P and drug entrapment of RIF (89.10%) and PTM (79.31%), respectively. FTIR analysis showed no interactions between components of RIF-PTM-PNP. Moreover, RIF-PTM-PNP-Gel was homogeneous, has optimal pH with desirable viscosity. The in-vitro release of RIF and PTM from RIF-PTM-PNP and RIF-PTM-PNP-Gel showed more sustained release behavior as compared to RIF and PTM solutions. Similarly, significantly higher skin penetration was observed in case of RIF-PTM-PNP and RIF-PTM-PNP-Gel, when compared with conventional gel. Additionally, RIF-PTM-PNP showed superior percent inhibition, higher macrophage uptake and lower IC₅₀ value against promastigotes in association with drugs solutions. Furthermore, in-vivo skin irritation and histopathology study indicated a safe and non-irritant behavior of the RIF-PTM-PNP-Gel, when compared with 0.8% formalin. Also, the optimized formulation (RIF-PTM-PNP) was found stable for at least 6 months. These findings suggested the successful preparation of co-loaded RIF-PTM-PNP and their incorporation into Carbopol-based RIF-PTM-PNP-Gel for topical administration with sustained drug release, enhanced skin permeation, macrophage uptake and improved antileishmanial effect.
Screening of potential hub genes involved in Cutaneous Leishmaniasis infection via bioinformatics analysis
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Cutaneous Leishmaniasis (CL) is the most common clinical form of leishmaniasis. Despite its low mortality, CL deserves further attention because its pathogenesis is currently no well-known or well-researched.
We downloaded the gene expression datasets of GSE55664 and GSE63931 with respect to leishmaniasis from the Gene Expression Synthesis (GEO) database. Additionally, the differentially expressed genes (DEGs) in the infection and control groups were identified by packages of R software. The Gene Ontology (GO) function, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) pathway were utilized for the biological functional analysis. Subsequently, we identified the top ten hub genes from protein-protein interaction (PPI) networks based on STRING and Cytoscape software. The hub genes were validated in GraphPad Prism 8.0 using the GSE162760 dataset. Further, CIBERSORT was used to evaluate the immune cell infiltration proportions between the CL infection samples and the control samples based on the GSE43880 and GSE55664 datasets.
The enrichment analysis revealed that DEGs were significantly involved in cell-mediated immune responses, such as leukocyte cell-cell adhesion and T-cell activation. STAT1, CCR7, CCR2, and CXCL10 were identified as hub genes with statistical significance. These hub genes showed close correlations with various immune cells, such as M1 cells and CD4-activated memory T-cells.
In our research, we used bioinformatics analysis to identify some molecular biomarkers and significant pathways in CL infection. These hub genes may provide new options for future diagnosis and treatment.
Treatment outcome of imported cutaneous leishmaniasis among travelers and migrants infected with Leishmania major and Leishmania tropica: a retrospective study in European centers 2013 to 2019
2022, International Journal of Infectious Diseases
Cutaneous leishmaniasis (CL) in Asia, Northern, and Sub-Saharan Africa is mainly caused by Leishmania major and Leishmania tropica. We describe and evaluate the treatment outcome of CL among travelers and migrants in Europe.
We conducted a retrospective study of parasitological confirmed CL cases caused by L. major and L. tropica during 2013-2019 in Europe. Data were collected from medical records and databases within the LeishMan network.
Of 206 included cases of CL, 75 were identified as L. major and 131 as L. tropica. Of patients with L. tropica infection, 80% were migrants, whereas 53% of patients with L. major infection had been visiting friends and relatives. Among patients with L. tropica, 48% were younger than 15 years. Pentavalent antimony cured 73% (L. major) and 78% (L. tropica) of patients. The cure rate for intralesional administration was 86% and 67% for systemic, on L. tropica. Liposomal amphotericin B had a cure rate of 44-63%.
L. major infections were mostly found in individuals visiting friends and relatives, whereas L. tropica were mainly identified in migrants. No patients with L. major relapsed. Pentavalent antimony, liposomal amphotericin B, and cryotherapy had cure rates in accordance with previous studies.
Recent advancements in anti-leishmanial research: Synthetic strategies and structural activity relationships
2021, European Journal of Medicinal Chemistry
Citation Excerpt :
Leishmaniasis can be categorized clinically into cutaneous leishmaniasis, visceral multiorgan leishmaniasis (kala-azar), localized leishmaniasis (infection of the lymph node) and mucogenic leishmaniasis. Among these, the cutaneous type is most prevalent whereas the visceral type is associated with serious complications and may be life-threatening if not treated timely [3,30–36]. Leishmania is a digenetic protozoan parasite that requires two hosts to complete its lifecycle.
Leishmaniasis is a parasitic neglected tropical disease caused by various species of Leishmania parasite. Despite tremendous advancements in the therapeutic sector and drug development strategies, still the existing anti-leishmanial agents are associated with some clinical issues like drug resistance, toxicity and selectivity. Therefore, several research groups are continuously working towards the development of new therapeutic candidates to overcome these issues. Many potential heterocyclic moieties have been explored for this purpose including triazoles, chalcones, chromone, thiazoles, thiosemicarbazones, indole, quinolines, etc. It is evident from the literature that the majority of anti-leishmanial agents act by interacting with key regulators including PTR-I, DHFR, LdMetAP1, MAPK, 14 α-demethylase and pteridine reductase-I, etc. Also, these tend to induce the production of ROS which causes damage to parasites. In the present compilation, authors have summarized various significant synthetic procedures for anti-leishmanial agents reported in recent years. A brief description of the pharmacological potentials of synthesized compounds along with important aspects related to structural activity relationship has been provided. Important docking outcomes highlighting the possible mode of interaction for the reported compounds have also been included. This review would be helpful to the scientific community to design newer strategies and also to develop novel therapeutic candidates against leishmaniasis.
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In addition to the infestations and bacterial infections reported in part I, the study of entomodermoscopy also involves descriptions of dermoscopic findings of a growing number of viral and fungal infections, among others. In this article, the main clinical situations in viral infections where dermoscopy can be useful will be described, that is in the evaluation of viral warts, molluscum contagiosum, and even in recent scenarios such as the COVID-19 pandemic. As for fungal infections, dermoscopy is particularly important, not only in the evaluation of the skin surface, but also of skin annexes, such as hairs and nails. The differential diagnosis with skin tumors, especially melanomas, can be facilitated by dermoscopy, especially in the evaluation of cases of verruca plantaris, onychomycosis and tinea nigra.

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Cutaneous leishmaniasis

Abstract

Introduction

Section snippets

Epidemiology

Etiology

Pathology

Clinical features

Differential diagnosis

Investigations

Treatment

Prevention

Summary

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