Candidate gene study of susceptibility to cutaneous leishmaniasis in Sri Lanka

Objectives To investigate the association between selected single nucleotide polymorphisms (SNPs) in TNF, LTA and SLC11A1 genes and risk of endemic cutaneous leishmaniasis (CL) in Sri Lanka through a case–control disease association study. Methods An anonymized DNA resource representative of the Sri Lankan population was genotyped initially to establish baseline parameters. This was followed up by genotyping 200 patients and 200 matched controls. Published or modified PCR/RFLP methods were employed for genotyping. Results Comparison of the different ethnic groups showed the distribution of alleles of LTA +252 A>G to differ significantly in Tamils and Moors when compared with Sinhalese. The differences seen at allele level were also reflected in the haplotypes defined by these SNPs at the TNF locus. The case–control analysis did not show an association between the SNPs or the haplotypes investigated and CL. The distribution of these variant alleles in other populations, where they are positively associated with leishmaniasis, differed significantly from the Sri Lankan study cohort. Conclusions The selected polymorphisms do not predispose to CL in the Sri Lankan population. The study of extended haplotypes at these loci using a sufficiently powered sample collection would elaborate the findings of this study. In the face of an evolving disease pattern in the country with other forms of leishmaniasis now being reported, prevalence of polymorphisms predisposing to these forms calls for heightened surveillance and preparedness.     

Clinical manifestations of cutaneous leishmaniasis in Sri Lanka - possible evidence for genetic susceptibility among the Sinhalese

Human cutaneous leishmaniasis (CL) caused by Leishmania donovani, a pathogen more usually associated with visceral leishmaniasis, is now endemic in Sri Lanka. This report details the characteristics of 200 patients with locally acquired CL, who were recruited prospectively for an ongoing study into the genetic susceptibility to CL in Sri Lanka. In each case, the CL was confirmed by the demonstration of amastigotes in a direct smear and/or promastigotes in a culture. Although only 82% of the Sri Lankan population is Sinhalese, all 200 patients belonged to this ethnic group. The patients had a median age of 32 years (range=4-80 years). Most of them each had a single, non-tender, non-itching and dry lesion which had started as a papule and then gradually enlarged and ulcerated, with changes in the surrounding skin. None of the patients had any signs of systemic disease. Eleven (5.5%) each had at least one other affected family member. Patients with multiple lesions were most likely to be found in families with more than one affected member (P=0.002) but multiple lesions were not associated with diabetes mellitus (P>0.05). Although the results of passive detection under-estimate the true occurrence of a disease, the present data point towards enhanced susceptibility to CL among the Sinhalese and/or certain individuals, possibly determined by genetic factors.     

Cross-Sectional Study to Assess Risk Factors for Leishmaniasis in an Endemic Region in Sri Lanka

Sri Lanka reports significantly more cutaneous leishmaniasis (CL) cases than visceral leishmaniasis (VL) cases, both of which are caused by Leishmania donovani MON-37. A cross-sectional study conducted in an area with a high prevalence of CL prevalent included 954 participants of an estimated population of 61,674 to estimate the number of CL cases, ascertain whether there is a pool of asymptomatic VL cases, and identify risk factors for transmission. A total of 31 cases of CL were identified, of whom 21 were previously diagnosed and 10 were new cases. Using rK39 rapid diagnostic test to detect antibodies against Leishmania spp., we found that only one person was seropositive but did not have clinical symptoms of CL or VL, which indicated low transmission of VL in this area. χ² test, independent sample t-test, and multivariate analysis of sociodemographic and spatial distribution of environmental risk factors showed that living near paddy fields is associated with increased risk for transmission of CL (P ≤ 0.01).     

In situ immunopathological changes in cutaneous leishmaniasis due to Leishmania donovani

Cutaneous leishmaniasis in Sri Lanka is a newly established parasitic disease caused by the usually visceralizing Leishmania donovani. Skin lesions manifest as non‐itchy, non‐tender papules, nodules or ulcers. In situ cytokine expression provides clues for immunopathogenesis of this localized form of disease. Skin biopsies from 58 patients were analyzed for histological appearance and in situ cytokine expression of T‐helper 1 (Th1) and T‐helper 2 (Th2) cytokines, namely interferon (IFN)‐γ, interleukin (IL)‐12A, tumor necrosis factor (TNF)‐α, IL‐4 and IL‐10 by real‐time RT‐PCR. Significant up‐regulation of the Th1 cytokine IFN‐γ and down‐regulation of the Th2 cytokine IL‐4 were seen in patients compared to healthy controls. Significantly elevated tissue expression of IFN‐γ and TNF‐α was seen in lesions that presented later than 6 months from the time of onset, while IL‐4 expression was more prominent in lesions that responded poorly to antimony therapy. A prominent Th1 response appears to support resolving of lesions, whereas a Th2‐biased milieu tends to favor poor responsiveness to antimony and delayed lesion healing in L. donovani infections in Sri Lanka.     

我国黑热病的流行概况和防治现状

黑热病又称内脏利什曼病,是严重危害人类身体健康的寄生虫病。按传染源特点可分为野生动物源型、犬源型和人源型3种类型。目前,人源型黑热病除新疆流行区外,在其他流行区已得到控制。而犬源型和野生动物源型黑热病则在其流行区不断出现,有死灰复燃之势。本文对我国黑热病的分型、流行概况和防治现状进行了综述。     

中国犬源性和野生动物源性内脏利什曼病的研究进展

我国内脏利什曼病在整个演化过程中反映出不同的流行病学特点,从原始野生动物经犬到人的三个演化阶梯,即野生动物源性内脏利什曼病、犬源性内脏利什曼病和人源性内脏利什曼病。我国陇南川北山区是内脏利什曼病自然疫源地和犬源性内脏利什曼病并存的疫区。人偶尔可直接从野生动物宿主经野生中华白蛉而感染,而更多的是野生动物宿主通过野生白蛉由犬再经白蛉传染给人。阐明这一传播关系,从理论上探讨内脏利什曼病的起源和演化规律,按其各自的特点和规律来制定计划,将对内脏利什曼病和媒介白蛉的预防与控制的实施具有重要指导意义。     

Advances in the treatment of leishmaniasis

PURPOSE OF REVIEW: Treatment of leishmaniasis is far from satisfactory: all antileishmanial drugs are toxic and most have to be used parenterally for prolonged periods, especially for visceral leishmaniasis. In recent years, there has been a steady erosion in the efficacy of pentavalent antimony to cure visceral leishmaniasis in Bihar, India. In addition, several new antileishmanial formulations have become available. RECENT FINDINGS: Through the publication of three studies from Africa, generic sodium stibogluconate, which is a fraction of the price of the branded drug Pentostam, has proven to be equivalent to Pentostam both in terms of safety and efficacy. The first oral drug, miltefosine, has been approved for treating visceral leishmaniasis in India, and preliminary reports of its efficacy against cutaneous leishmaniasis have been published. Interesting studies on successful low/single dose treatment of Indian visceral leishmaniasis with liposomal amphotericin B have been published. Several trials using different approaches towards treating cutaneous leishmaniasis are also reviewed. The results of clinical trials of two oral compounds are reported - fluconazole in treating cutaneous leishmaniasis was found to be safe and effective, whereas sitamaquine (WR6026) for visceral leishmaniasis was found to be toxic with poor efficacy. SUMMARY: Generic stibogluconate enables the cost effective treatment of all forms of leishmaniasis as it remains the most important antileishmanial drug in most parts of the world. In India, successful single dose AmBisome for visceral leishmaniasis makes therapy simple and enables mass treatment, provided the drug cost is brought down. For cutaneous leishmaniasis, two new oral drugs, fluconazole and miltefosine, provide wider options to the clinician.     

2018年全国内脏利什曼病疫情分析

目的了解2018年全国内脏利什曼病的疫情状况。方法收集2018年中国疾病预防控制中心传染病报告信息管理系统中全国内脏利什曼病病例信息,剔除疑似病例、重复病例以及皮肤利什曼病病例,建立数据库,采用Microsoft Excel 2016软件对内脏利什曼病病例的三间分布进行描述性流行病学分析。结果2018年全国11个省份的78个县共报告内脏利什曼病180例,病例主要分布于甘肃(66例)、山西(38例)和陕西(27例)等3个省。其中40个县属于流行区,共报告本地感染病例134例,其余38个县属于非流行区,共报告输入性病例46例。其中甘肃省舟曲县(22例)、宕昌县(18例)和武都区(10例)为主要流行县,报告病例占全国总报告病例数的27.8%(50/180)。陕西省渭南市化州区和临渭区再现本地感染病例,为内脏利什曼病复燃流行县。内脏利什曼病发病高峰为4-6月,男女病例比为1∶0.7。农民和儿童是我国内脏利什曼病高风险人群,分别占全部病例数的42.2%(76/180)和34.5%(55/180)。内脏利什曼病病例主要分布于≥15岁年龄组,不同流行类型病例年龄分布明显不同,野生动物源型病例主要分布于0~2岁婴幼儿,人源型与犬源型病例主要分布于≥15岁农民。结论我国内脏利什曼病呈低度流行态势,但流行区范围逐渐蔓延。     

Disseminated cutaneous leishmaniasis due to Leishmania guyanensis: case of a patient with 425 lesions

Disseminated cutaneous leishmaniasis is characterized by the presence of a large (> or =10) number of lesions at several anatomic sites (head, limbs, and trunk). Most of the lesions are small, papular, and appear simultaneously with or secondarily to one or several ulcerated lesions of localized cutaneous leishmaniasis. We report the first case of disseminated cutaneous leishmaniasis in French Guiana. It concerns a 24-year-old woman who tested negative for human immunodeficiency virus (HIV). The disease began with three lesions that became ulcerated. One week later, multiple papulo-nodular lesions appeared. We counted a total of 425 lesions. Leishmania were observed in the lesions. The species involved was L. guyanensis, which has never been described in a case of disseminated cutaneous leishmaniasis. The patient was rapidly cured by a single course of pentamidine. Disseminated cutaneous leishmaniasis should be distinguished from other types of leishmaniasis with multiple lesions. These include anergic diffuse cutaneous leishmaniasis, post-kala-azar leishmaniasis, and leishmaniasis associated with HIV infection.     

Cutaneous leishmaniasis in the returning traveler

Infection with protozoan parasites of the genus Leishmania leads to a wide variety of clinical disease syndromes called leishmaniasis, or more appropriately the leishmaniases. The three major clinical syndromes are cutaneous leishmaniasis, mucosal leishmaniasis, and visceral leishmaniasis. All three of these syndromes have been documented in returning travelers. This article focuses on cutaneous leishmaniasis with some comment on mucosal leishmaniasis.     

Leishmaniasis in the Argentine Republic: Temporal and geographical distribution from 2013 to 2017

Objective: To assess the temporal and geographical distribution of confirmed cases of cutaneous, mucocutaneous and visceral leishmaniasis in the Argentine Republic from 2013 to 2017. Methods: A retrospective study was carried out using data collected from the Integrated Surveillance Bulletin database of the National System of Health Surveillance. Confirmed cases of cutaneous, mucocutaneous and visceral leishmaniasis up to the 52 nd epidemiological week of each year was included. Results: In the 5 years period, 1 295 confirmed leishmaniasis cases were reported in the Argentine Republic. One thousand twenty-eight(1 028) cases corresponded to cutaneous leishmaniasis(87.10%), being the most common type of leishmaniasis. Mucocutaneous leishmaniasis was in the second place in the country with 115 cases reported, mostly in the Northwest and Northeast regions. A total of 52 individuals with visceral leishmaniasis were identified and Misiones Province was the most affected. Conclusions: It is important to analyze the temporal and geographical distribution of leishmaniasis in order to provide an adequate management and surveillance.     

Vascular changes in human leishmaniasis: a light microscope and immunohistological study

The study of human cutaneous leishmaniasis from Saudi Arabia (37 cases), and of Sudanese mucosal (52 cases) and visceral (27 cases) leishmaniasis revealed the occurrence of vascular alterations. Vasculitis with or without fibrinoid necrosis and fibrin thrombi were found in both the arteries and veins within the area of inflammation in cutaneous and mucosal leishmaniasis; whereas subendothelial oedema, hyalinosis and intimaproliferation were seen in the small arteries of the various organs in visceral leishmaniasis. Immunoperoxidase staining of the cutaneous leishmaniasis lesions showed the presence of IgG and IgA within the endothelial cells, in the media, and in the perivascular space of the diseased vessels. The formation of immune complexes, locally in cutaneous and mucosal leishmaniasis and circulating in visceral leishmaniasis, is considered responsible for these vascular lesions.     

Kidney involvement in leishmaniasis—a review

Leishmaniasis is an infectious disease caused by protozoa of the genus Leishmania transmitted by insects of the genus Lutzomyia sp. or Phlebotomus sp. The main syndromes are cutaneous leishmaniasis, mucocutaneous leishmaniasis, visceral leishmaniasis (kala-azar) and post-kala-azar dermal leishmaniasis. This article reviews kidney involvement in cutaneous and visceral leishmaniasis, highlighting the aspects of their pathophysiology, clinical manifestations, histopathological findings, outcome and treatment.     

Cutaneous leishmaniasis treatment

The causative species of cutaneous leishmaniasis determines the clinical features and courses, and treatments. Intralesional or systemic antimonials are the gold standard for the treatment of these diseases. However, as for visceral leishmaniasis, other therapeutic options appear promising. Paromomycin ointments are effective in Leishmania major, L. tropica, L. mexicana, and L. panamensis lesions. In L. braziliensis localized leishmaniasis, both paromomycin and imiquimod may be topically applied. Oral fluconazole and zinc sulfate are useful in L. major. Oral azithromycin, effective in vitro and in mice, needs further investigation in human leishmaniasis. On the contrary, data with oral itraconazole are disappointing. Oral miltefosine, which is very effective in visceral leishmaniasis caused by L. donovani, appears ineffective in L. major and L. braziliensis infections. Intramuscular pentamidine is required for L. guyanensis cutaneous leishmaniasis, for which systemic antimony is not effective. Liposomal amphotericin B could be an alternative to antimony in south American cutaneous leishmaniasis with mucosal involvement (especially L. braziliensis and L. guyanensis infections).     

Immunology of canine leishmaniasis

The role of dogs as the main reservoir of visceral leishmaniasis has led to an increased interest in the immune responses and in Leishmania antigens implicated in protective cellular immunity in canine visceral leishmaniasis. The primary goal is to control the prevalence of human disease. Immune responses in canine visceral leishmaniasis are reviewed. Cellular immune responses toward a Th1 subset mediated by IFN-gamma and TNF-alpha predominate in asymptomatic dogs exhibiting apparent resistance to visceral leishmaniasis. On the other hand, while the role of Th2 cytokines, such as IL-4 and IL-10, in symptomatic animals is still controversial, there is increasing evidence for a correlation of these cytokines with progressive disease. CD8+ cytotoxic T cells seem also likely to be involved in resistance to visceral leishmaniasis. Several Leishmania antigens implicated in protective immune responses are described and some pivotal points for development of an effective vaccine against canine visceral leishmaniasis are discussed.     

Leishmaniasis in rheumatoid arthritis

Leishmaniasis represents a complex of diseases with an important clinical and epidemiological diversity. Visceral leishmaniasis is of higher priority than cutaneous leishmaniasis as it is a fatal disease in the absence of treatment. The clinical spectrum of leishmaniasis and control of the infection are influenced by the parasite-host relationship. The role of cellular immune responses of the Th1 type in the protection against disease in experimental and human leishmaniasis is well established. TNF-alpha has been implicated in cytokine-induced macrophage activation and tissue granuloma formation, two activities linked to control of intracellular visceral infection caused by Leishmania donovani. Anti-tumor necrosis factor-alpha (TNF-alpha) strategies have had a marked and substantial impact in the treatment of rheumatoid arthritis, however the clinical use of TNF-alpha antagonists has been accompanied by increased reporting of infections. Here we report the first case of visceral leishmaniasis in a patient treated for a long period of time with human anti TNF-alpha monoclonal antibody, adalimumab. Due to the low incidence rate of Mediterranean visceral leishmaniasis, a systematic screening for leishmaniasis in all patients treated with biologics may be not recommended. However, for those patients living at high risk of leishmaniasis exposure, a periodical serological monitoring should be performed during therapy with anti-TNF monoclonal antibodies.     

Bone marrow leishmaniasis: a review of situation in Thailand

Leishmaniasis is an important tropical vector-borne disease. This infection can be seen in tropical area and it is considered to be one of the most important vector-borne infections at present. The general situation of the leishmaniasis in Thailand is hereby reviewed. Although Thailand is a tropical country, the leishmaniasis is not endemic but sporadic. The imported cases are documented in some literatures. The serious form of leishmaniasis, the visceral leishmaniasis is also detectable in Thailand. Also, the author performed an in depth literature review of the reports of bone marrow leishmaniasis, a specific kind of visceral leishmaniasis, in Thailand in order to summarize the characteristics of this infection among Thai patients. According to this review, there have been at least 5 reports in the literature of 6 cases of bone marrow leishmaniasis in the Thai population, of which no case was lethal. Concerning the clinical manifestations, all except had prolonged fever with unknown origin. From physical examination, all had hepatosplenomegaly. The striking findings were active hemophagocytosis with increased proliferation of lymphoidplasma cell line in the bone marrow and amastigotes of Leishmania donovani was demonstrated. Considering the treatment, pantavalent antimony compound was used and the excellent improvement and complete recovery. Finally, the author also discussed on the importance of leishmaniasis in Thailand relating to the present globalization and good traveling system.     

我国输入性利什曼病传播风险矩阵评估研究

目的 构建输入性利什曼病传播风险评估体系,为评估我国输入性利什曼病的传播风险提供科学依据。方法 运用专家咨询法,构建输入性利什曼病传播风险评价指标体系,应用风险矩阵评估方法评价我国输入性利什曼病的传播风险等级。结果 通过专家咨询法建立了我国输入性利什曼病传播风险评价指标体系,其中风险发生可能性评价体系包括3个一级指标、13个二级指标,风险危害程度评价体系包括5个指标。经风险矩阵分析评估,目前我国输入性利什曼病传播风险等级为低风险。结论 本研究首次使用矩阵分析方法进行输入性利什曼病的传播风险分析,提示我国存在输入性利什曼病传播的潜在风险。     

利什曼病及其媒介白蛉控制的现状和展望

利什曼病是我国重要的寄生虫病之一，白蛉是其传播媒介，目前我国已发现有4种白蛉可传播利什曼病。近几年，世界范围内利什曼病的发病率呈上升趋势，这不仅由于环境改变增加了人与白蛉接触的机会，而且由于个体危险因素的增加，缩短了从感染到发病的时间。该文借鉴国外利什曼病的防治经验，结合我国的国情，对加强利什曼病的防治以及媒介白蛉的控制工作提出了建议。