Showing papers on "Visceral leishmaniasis published in 2001"
TL;DR: Evaluation of diagnostic methods showed that parasitological diagnosis should still be the mainstay in diagnosis, with sensitivities for lymph node, bone marrow and spleen aspirates of 58%, 70% and 96%, respectively, and simple, cheap serological tests are needed.
Abstract: From the early 1900s, visceral leishmaniasis (VL; kala-azar) has been among the most important health problems in Sudan, particularly in the main endemic area in the eastern and central regions. Several major epidemics have occurred, the most recent--in Western Upper Nile province in southern Sudan, detected in 1988--claiming over 100,000 lives. The disease spread to other areas that were previously not known to be endemic for VL. A major upsurge in the number of cases was noted in the endemic area. These events triggered renewed interest in the disease. Epidemiological and entomological studies confirmed Phlebotomus orientalis as the vector in several parts of the country, typically associated with Acacia seyal and Balanites aegyptiaca vegetation. Infection rates with Leishmania were high, but subject to seasonal variation, as were the numbers of sand flies. Parasites isolated from humans and sand flies belonged to three zymodemes (MON-18, MON-30 and MON-82), which all belong to the L. donovani sensu lato cluster. Transmission dynamics have not been elucidated fully; heavy transmission in relatively scarcely populated areas such as Dinder national park suggested zoonotic transmission whereas the large numbers of patients with post kala-azar dermal leishmaniasis (PKDL) in heavily affected villages may indicate a human reservoir and anthroponotic transmission. Clinical presentation in adults and in children did not differ significantly, except that children were more anaemic. Fever, weight loss, hepato-splenomegaly and lymphadenopathy were the most common findings. PKDL was much more common than expected (56% of patients with VL developed PKDL), but other post-VL manifestations were also found affecting the eyes (uveitis, conjunctivitis, blepharitis), nasal and/or oral mucosa. Evaluation of diagnostic methods showed that parasitological diagnosis should still be the mainstay in diagnosis, with sensitivities for lymph node, bone marrow and spleen aspirates of 58%, 70% and 96%, respectively. Simple, cheap serological tests are needed. The direct agglutination test (DAT) had a sensitivity of 72%, specificity of 94%, positive predictive value of 78% and negative predictive value of 92%. As with other serological tests, the DAT cannot distinguish between active disease, subclinical infection or past infection. The introduction of freeze-dried antigen and control sera greatly improved the practicality and accuracy of the DAT in the field. An enzyme-linked immunosorbent assay using recombinant K39 antigen had higher sensitivity than DAT (93%). The polymerase chain reaction using peripheral blood gave a sensitivity of 70-93% and was more sensitive than microscopy of lymph node or bone marrow aspirates in patients with suspected VL. The leishmanin skin test (LST) was typically negative during active VL and converted to positive in c. 80% of patients 6 months after treatment. Immunological studies showed that both Th1 and Th2 cell responses could be demonstrated in lymph nodes from VL patients as evidenced by the presence of messenger ribonucleic acid for interleukin (IL)-10, interferon gamma and IL-2. Treatment of peripheral blood mononuclear cells from VL patients with IL-12 was found to drive the immune response toward a Th1 type response with the production of interferon gamma, indicating a potential therapeutic role for IL-12. VL responded well to treatment with sodium stibogluconate, which is still the first line drug at a dose of 20 mg/kg intravenously or intramuscularly per day for 15-30 d. Side effects and resistance were rare. Liposomal amphotericin B was effective, with few side effects. Control measures have not been implemented. Based on observations that VL does not occur in individuals who have a positive LST, probably because of previous cutaneous leishmaniasis, a vaccine containing heat-killed L. major promastigotes is currently undergoing a phase III trial.
489 citations
TL;DR: It is demonstrated that murine and human macrophages produce O2− during phagocytosis of opsonized promastigotes and NO· each contribute to intracellular killing of L. chagasi in human and murine macrophage.
Abstract: Leishmania chagasi, the cause of South American visceral leishmaniasis, must survive antimicrobial responses of host macrophages to establish infection. Macrophage oxidative responses have been shown to diminish in the presence of intracellular leishmania. However, using electron spin resonance we demonstrated that murine and human macrophages produce O2-during phagocytosis of opsonized promastigotes. Addition of the O2- scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl to cultures resulted in increased infection, suggesting that O2- enhances macrophage leishmanicidal activity. The importance of NO. produced by inducible NO synthase (iNOS) in controlling murine leishmaniasis is established, but its role in human macrophages has been debated. We detected NO. in supernatants from murine, but not human, macrophages infected with L. chagasi. Nonetheless, the iNOS inhibitor N(G)-monomethyl-L-arginine inhibited IFN-gamma-mediated intracellular killing by both murine and human macrophages. According to RNase protection assay and immunohistochemistry, iNOS mRNA and protein were expressed at higher levels in bone marrow of patients with visceral leishmaniasis than in controls. The iNOS protein also increased upon infection of human macrophages with L. chagasi promastigotes in vitro in the presence of IFN-gamma. These data suggest that O2- and NO. each contribute to intracellular killing of L. chagasi in human and murine macrophages.
293 citations
TL;DR: Although a Th1-like cytokine response was prominent, the major antileishmanial effector mechanism that is responsible for control of infection in mice was absent throughout the course of progressive VL in the hamster.
Abstract: Active human visceral leishmaniasis (VL) is characterized by a progressive increase in visceral parasite burden, cachexia, massive splenomegaly, and hypergammaglobulinemia. In contrast, mice infected with Leishmania donovani, the most commonly studied model of VL, do not develop overt, progressive disease. Furthermore, mice control Leishmania infection through the generation of NO, an effector mechanism that does not have a clear role in human macrophage antimicrobial function. Remarkably, infection of the Syrian hamster (Mesocricetus auratus) with L. donovani reproduced the clinicopathological features of human VL, and investigation into the mechanisms of disease in the hamster revealed striking differences from the murine model. Uncontrolled parasite replication in the hamster liver, spleen, and bone marrow occurred despite a strong Th1-like cytokine (IL-2, IFN-gamma, and TNF/lymphotoxin) response in these organs, suggesting impairment of macrophage effector function. Indeed, throughout the course of infection, inducible NO synthase (iNOS, NOS2) mRNA or enzyme activity in liver or spleen tissue was not detected. In contrast, NOS2 mRNA and enzyme activity was readily detected in the spleens of infected mice. The impaired hamster NOS2 expression could not be explained by an absence of the NOS2 gene, overproduction of IL-4, defective TNF/lymphotoxin production (a potent second signal for NOS2 induction), or early dominant production of the deactivating cytokines IL-10 and TGF-beta. Thus, although a Th1-like cytokine response was prominent, the major antileishmanial effector mechanism that is responsible for control of infection in mice was absent throughout the course of progressive VL in the hamster.
268 citations
TL;DR: Although leishmaniasis could contribute to death in a significant number of HIV-infected patients, it was the main cause of death in only a few of them and should be considered as an AIDS-defining disease.
237 citations
TL;DR: If the initial Th1-cell-associated immune response fails to develop or its effector mechanisms are disabled or not properly maintained, recently acquired kala-azar evolves to full expression as a subacute or chronic illness for which treatment is required.
Abstract: Visceral leishmaniaisis (kala-azar) is a disseminated protozoal infection transmitted by sandfly bite in which macrophages of the liver spleen and bone marrow are preferentially parasitized and support intracellular replication. Most human infections caused by visceralizing strains of Leishmania are probably subclinical attesting to innate resistance or more likely to T (Th1)-cell-dependent immune responses which induce acquired resistance. While treatment is not given for subclinical infection remote recrudescence still remains a possibility especially if the host becomes T-cell deficient. In contrast if the initial Th1-cell-associated immune response fails to develop or its effector mechanisms are disabled or not properly maintained recently acquired (or reactivated) kala-azar evolves to full expression as a subacute or chronic illness for which treatment is required. (excerpt)
231 citations
TL;DR: The age distribution of visceral leishmaniasis cases in the MRBH shows a higher prevalence in children from 0-4 years old, responsible for 28.9% of the notifications, and an urbanization of the disease in this region of Minas Gerais.
Abstract: In the last few years the number of human cases of American visceral leishmaniasis in the Metropolitan Region of Belo Horizonte (MRBH), Minas Gerais, Brazil has increased, indicating an elevation in the transmission rate of the disease. The total number of notified human cases in the MRBH since 1994, when the first case was identified, up to 1999 was 345 of which 223 (65%) were from the city itself, indicating an urbanization of the disease in this region of Minas Gerais. The age distribution of visceral leishmaniasis cases in the MRBH shows a higher prevalence in children from 0-4 years old, responsible for 28.9% of the notifications. Clinical and immunological findings from dogs infected with Leishmania chagasi are described. The majority of these animals showed no sign of the disease. Sera from all infected dogs showed detectable Leishmania-induced high titles of antibodies based on the results of an indirect fluorescent antibody test. Samples of isolated Leishmania from human and dogs were characterized as L. (L.) chagasi by biochemical and molecular techniques.
194 citations
TL;DR: It is demonstrated that resistant C57BL/6 (B6.WT) mice locally infected with L. major rapidly succumb to progressive visceral leishmaniasis after deletion of the TNF gene by homologous recombination, the first data to demonstrate that TNF is essential for the in vivo control of L.major.
Abstract: The resolution of infections with the protozoan parasite Leishmania major in mice requires a Th1 response that is closely associated with the expression of IL-12, IFN-γ, and inducible NO synthase. Previous Ab neutralization studies or the use of mice deficient for both TNF receptors suggested that TNF plays only a limited role in the control of parasite replication in vivo. In this study we demonstrate that resistant C57BL/6 (B6.WT) mice locally infected with L. major rapidly succumb to progressive visceral leishmaniasis after deletion of the TNF gene by homologous recombination. A reduction of the parasite inoculum to 3000 promastigotes did not prevent the fatal outcome of the disease. An influence of the altered morphology of secondary lymphoid organs in C57BL/6-TNF−/− (B6.TNF−/−) mice on the course of disease could be excluded by the generation of reciprocal bone marrow chimeras. Although infected B6.TNF−/− mice mounted an L. major -specific IFN-γ response and expressed IL-12, the onset of the immune reaction was delayed. After in vitro stimulation, B6.TNF−/− inflammatory macrophages released 10-fold less NO in response to IFN-γ than B6.WT cells. However, in the presence of a costimulus, e.g., L. major infection or LPS, the production of NO by B6.WT and B6.TNF−/− macrophages was comparable. In vivo, inducible NO synthase protein was readily detectable in skin lesions and draining lymph nodes of B6.TNF−/− mice, but its expression was more disperse and less focal in the absence of TNF. These are the first data to demonstrate that TNF is essential for the in vivo control of L. major .
182 citations
TL;DR: It is demonstrated here that although the LACK DNA vaccine induced a robust parasite-specific Th1 immune response and primed for an in vivo T-cell response to inoculated parasites, it did not induce protection against cutaneous or systemic L. major infection.
Abstract: The acquisition of immunity following subclinical or resolved infection with the intracellular parasite Leishmania donovani suggests that vaccination could prevent visceral leishmaniasis (VL). The LACK (Leishmania homolog of receptors for activated C kinase) antigen is of interest as a vaccine candidate for the leishmaniases because of its immunopathogenic role in murine L. major infection. Immunization of mice with a truncated (24-kDa) version of the 36-kDa LACK antigen, delivered in either protein or DNA form, was found previously to protect against cutaneous L. major infection by redirecting the early T-cell response away from a pathogenic interleukin-4 (IL-4) response and toward a protective Th1 response. The amino acid sequence of the Leishmania p36(LACK) antigen is highly conserved, but the efficacy of this vaccine antigen in preventing disease caused by strains other than L. major has not been determined. We investigated the efficacy of a p36(LACK) DNA vaccine against VL because of the serious nature of this form of leishmaniasis and because it was unclear whether the LACK vaccine would be effective in a model where there was not a dominant pathogenic IL-4 response. We demonstrate here that although the LACK DNA vaccine induced a robust parasite-specific Th1 immune response (IFN-gamma but not IL-4 production) and primed for an in vivo T-cell response to inoculated parasites, it did not induce protection against cutaneous or systemic L. donovani challenge. Coadministration of IL-12 DNA with the vaccine did not enhance the strong vaccine-induced Th1 response or augment a protective effect.
174 citations
TL;DR: Low dose liposomal amphotericin B (5 mg/kg), given either as a five day course or as a single infusion, seems to be effective for visceral leishmaniasis and warrants further testing.
Abstract: # Treatment of Indian visceral leishmaniasis with single or daily infusions of low dose liposomal amphotericin B: randomised trial {#article-title-2}
Objective: To test short course, low dose liposomal amphotericin B as single or daily infusion treatment in Indian visceral leishmaniasis (kala-azar).
Design: Randomised, open label study.
Setting: Inpatient unit for leishmaniasis in Bihar, India.
Participants: 91 adults and children with splenic aspirate positive for infection.
Interventions: Total dose of 5 mg/kg of liposomal amphotericin B given as a single infusion (n=46) or as once daily infusions of 1 mg/kg for five days (n=45).
Main outcome measures: Clinical and parasitological cure assessed 14 days after treatment and long term definitive cure (healthy, no relapse) at six months.
Results: All but one person in each group had an initial apparent cure. During six months of follow up, three patients in the single dose group and two in the five dose group relapsed. Complete response (definitive cure) was therefore achieved in 84 of 91 subjects (92%): 42 of 46 patients in the single dose group (91%, 95% confidence interval 79% to 98%) and 42 of 45 in the five dose group (93%, 82% to 99%). Response rates in the two groups were not significantly different.
Conclusion: Low dose liposomal amphotericin B (5 mg/kg), given either as a five day course or as a single infusion, seems to be effective for visceral leishmaniasis and warrants further testing.
# Commentary: cost and resistance remain issues {#article-title-19}
171 citations
TL;DR: Malnutrition causes a failure of lymph node barrier function after L. donovani infection, which may be related to excessive production of PGE2and decreased levels of IL-10 and nitric oxide.
Abstract: Globally, protein-energy malnutrition is the most frequent cause of immunodeficiency (58). Epidemiologic and experimental studies have documented an increased risk for visceral leishmaniasis, caused by intracellular protozoan parasites of the Leishmania donovani complex, in the malnourished host (1, 2, 26). However, the immunologic basis for this association has not been established and standardized experimental models have not addressed this important issue.
In this study, our goal was to investigate the mechanisms of the malnutrition-related susceptibility to visceral leishmaniasis. There were three components of the study. First, we needed to create a murine model of malnutrition that was relevant to human malnutrition in developing countries. Although the mouse has been extensively used in animal models of malnutrition, there is no standard murine model of protein-energy malnutrition (69). Human malnutrition is complex, typically involving deficiency of protein and energy with superimposed deficits of other nutrients. Zinc deficiency usually accompanies protein-energy malnutrition (19). Iron deficiency is highly prevalent in developing countries and may accompany zinc deficiency due to a common risk factor, cereal-based diets with little meat (61). Thus, in this model, in addition to protein and energy, zinc and iron were selected as deficient nutrients.
Much of the vast body of data that has been collected on human malnutrition is based on anthropometric measures, i.e., weight-for-age (WA), height-for-age, and weight-for-height (13). However, in previous mouse models of malnutrition, there have been no efforts to relate morphometric measures of nutritional status to either human anthropometric scales or immunocompetence. Weight-for-age determination is advantageous because it can be measured unambiguously, provides a synthesis of linear growth and body proportion (13), and correlates with probability of death in children in developing countries (36). In this study, murine WA was correlated with specific measures of host defense and risk for visceral L. donovani infection.
A second component of the study was to examine possible defects in the mediator network of the innate immune system produced by malnutrition, because it is the early events that are likely to determine whether the inoculated parasites are controlled locally or disseminate to visceral organs. The innate immune system provides a first line of defense against pathogens and instructs the differentiation of Th0 cells into Th1 and Th2 cells (18). It has been estimated that the innate immune system provides protection against 98% of the pathogens that are encountered (34). Malnutrition has been associated with an increased risk of many infections (3); however, there are no animal models that specifically examine the effect of malnutrition on the innate immune response to infection.
The third part of the study was to investigate the mechanism of visceralization (the process whereby parasites disseminate from the site of cutaneous inoculation and the draining lymph nodes to the liver, spleen, and bone marrow). To reach this goal, we needed to develop a more natural animal model of visceral leishmaniasis, using the vector stage of the parasite (promastigote) and the intradermal route of infection. Although the immunopathogenesis of murine visceral leishmaniasis has been investigated, previous studies have used an unnatural (intravenous) route of infection and/or the mammalian host stage of the parasite (amastigote) as the infecting inoculum (35, 40, 43, 48, 65). The intravenous route of inoculation negates the immune processing that would occur in the skin and in the draining lymph node and therefore does not accurately reflect the immune response that would occur in a natural cutaneous infection. Furthermore, models of visceral leishmaniasis that utilize the intravenous route of inoculation do not facilitate an understanding of the mechanism of visceralization. Selection of either amastigote or promastigote as the infective inoculum may also have an important bearing on the course of infection, because these two stages of the parasite possess disparate virulence factors (9) and produce different immune responses (20).
In this study, we establish a murine model of polynutrient deficiency that is similar to human malnutrition in developing regions of the world. We demonstrate that the malnourished mouse has an altered innate immune defense and is at increased risk of visceralization following cutaneous L. donovani infection.
170 citations
TL;DR: In anthroponotic areas reduction in transmission through public health measures will be important, but the use of two drugs in combination should be seriously considered, including miltefosine plus paromomycin and allopurinol plus an azole.
Abstract: At the moment no country has a policy designed to control or prevent drug resistance in leishmaniasis. The risk of resistance is high in areas of anthroponotic visceral leishmaniasis, for example North Bihar, India, where the rate in some areas is 60%. Post-epidemic Sudan is also at risk. Zoonotic areas in which HIV co-infection is common could also be at risk as sandflies can become infected from co-infected individuals. Many factors determine the choice of drug for the treatment of visceral leishmaniasis, and drug resistance may not be the over-riding priority. In anthroponotic areas reduction in transmission through public health measures will be important, but the use of two drugs in combination should be seriously considered. Pharmacokinetic and other features of the drugs available, relevant to their use in combination are discussed and tentative suggestions made concerning trials of possible combinations. These include miltefosine plus paromomycin and allopurinol plus an azole. Lessons may be learnt from the experiences of similar problems in malaria, leprosy and tuberculosis. Guidelines are offered for the introduction of policies to use drugs in combination, which differ between anthroponotic and zoonotic areas of transmission.
TL;DR: Compared to microscopy, KATEX performed better than any single serological test in predicting positivity and a particularly good result was obtained by combining KATEx and the direct agglutination test (DAT).
TL;DR: It is shown that immunization of mice with recombinant A2 protein conferred significant protection against challenge infection with Leishmania donovani, and A2 represents a potential antigen for protection against infection with L.Donovani and VL.
TL;DR: Mucosal leishmaniasis in Sudan is a chronic infection of the upper respiratory tract and/or oral mucosa caused mainly by Leishmania donovani and responds well to treatment with pentavalent antimony compounds.
Abstract: Sudanese mucosal leishmaniasis is a chronic infection of the upper respiratory tract and/or oral mucosa caused mainly by Leishmania donovani. The disease occurs in areas of the country endemic for visceral leishmaniasis, particularly among Masalit and other closely related tribes in western Sudan. The condition may develop during or after an attack of visceral leishmaniasis, but in most cases it is a primary mucosal disease. Unlike South American mucocutaneous leishmaniasis, mucosal leishmaniasis in Sudan is not preceded or accompanied by a cutaneous lesion. Pathologically, the lesions show a mixture of macrophages, plasma cells and lymphocytes. An epithelioid granuloma may also be found. Parasites are scanty. Diagnosis is established by demonstration of parasites in smears or biopsies, by culture or animal inoculation, or with the aid of the polymerase chain reaction. Most patients give positive results in the direct agglutination test and leishmanin skin test. Patients respond well to treatment with pentavalent antimony compounds.
TL;DR: These findings indicate that MBL can modulate the clinical outcome of infection with L. chagasi and the function of infected macrophages.
Abstract: Levels of the serum opsonin mannan-binding lectin (MBL) were directly correlated with the probability of developing visceral leishmaniasis. Monocytes infected with MBL-opsonized Leishmania chagasi promastigotes secreted higher levels of tumor necrosis factor alpha and interleukin-6 than cells infected with nonopsonized parasites. Our findings indicate that MBL can modulate the clinical outcome of infection with L. chagasi and the function of infected macrophages.
TL;DR: A case of visceral leishmaniasis in a 15-month-old German child with no history of travel to known endemic areas is described and possible modes of transmission are discussed.
Abstract: We describe a case of visceral leishmaniasis in a 15-month-old German child. Diagnosis was significantly delayed because the patient had no history of travel to known endemic areas. Congenital or blood transfusion-associated leishmaniasis was ruled out. Possible modes of transmission (including a potential new autochthonous focus of the disease in central Europe) are discussed.
TL;DR: The parasitic loads of mouse livers experimentally infected with Leishmania infantum were determined using a double real-time quantitative PCR test targeted to the parasite DNA polymerase gene and to the mouse brain-derived neutrophic factor gene.
Abstract: The parasitic loads of mouse livers experimentally infected with Leishmania infantum were determined using a double real-time quantitative PCR test targeted to the parasite DNA polymerase gene and to the mouse brain-derived neutrophic factor gene. The Leishmania DNA copy number was normalized to the number of mouse gene copies in order to quantify the former independently of liver weight. The correlation coefficient with the microtitration method was 0.66. This PCR assay can be considered for experimental pharmaceutical studies. The leishmaniases are a group of parasitic diseases of major and growing public health importance (9). Standard therapies include pentavalent antimonials and amphotericin B. These drugs cause secondary side effects, and relapses are frequent. Therefore, other antileishmanial compounds (11) or new formulations of existing ones (14) are needed. Mouse inoculation is the most used in vivo model of visceral leishmaniasis for the evaluation of anti-Leishmania drugs (5‐7, 16). Assessment of parasitic burdens is usually based on microscopic enumerations of amastigotes against host cell nuclei on liver imprints (15). This type of assay is time-consuming and subjective and is not reliable when the parasites are not equally dispersed on the slides. More recently, culture microtitrations have been developed (2, 17). These techniques are more sensitive than the imprint method, but the assays remain laborintensive. Since recurrences of leishmaniasis are associated with tissue loads of residual, latent parasites after treatment, nonquantitative PCR tests (3, 12, 13) are of little value in indicating a positive or negative result. A recent approach for quantitation of DNA copy number is based on the 59 nuclease activity of Taq polymerase for fragmentation of a dual-labeled fluorogenic hybridization probe (8). A real-time quantitative TaqMan PCR assay for measuring the copy numbers of Leishmania infantum DNA in mouse liver was developed. A first possibility was to use absolute quantitation. This requires the design of standards known by independent means. Several critical points must be considered, such as the reliability of the serial dilutions of the parasites, the accuracy of pipetting, and the stability of the diluted standards. For the present purpose, i.e., to quantify L. infantum in mouse tissues, very precise weighing of liver biopsy specimens is also necessary. Another possibility was to use relative quantification using the DDCt method (1). In this system, each sample tested is normalized on the basis of its mouse DNA content, and the result is indepen
TL;DR: Data suggest that clinical symptoms are not due to a deficiency in interferon-gamma production, however, in contrast to its role in human visceral leishmaniasis, IL-10 may not play a key immunosuppressive role in dogs.
Abstract: To elucidate the local tissue cytokine response of dogs infected with Leishmania chagasi, cytokine mRNA levels were measured in bone marrow aspirates from 27 naturally infected dogs from Brazil and were compared with those from 5 uninfected control animals. Interferon-gamma mRNA accumulation was enhanced in infected dogs and was positively correlated with humoral (IgG1) but not with lymphoproliferative responses to Leishmania antigen in infected dogs. Increased accumulation of mRNA for interleukin (IL)-4, IL-10, and IL-18 was not observed in infected dogs, and mRNA for these cytokines did not correlate with antibody or proliferative responses. However, infected dogs with detectable IL-4 mRNA had significantly more severe symptoms. IL-13 mRNA was not detectable in either control or infected dogs. These data suggest that clinical symptoms are not due to a deficiency in interferon-gamma production. However, in contrast to its role in human visceral leishmaniasis, IL-10 may not play a key immunosuppressive role in dogs.
01 Dec 2001
TL;DR: In the last two decades, leishmaniasis, especially visceral leish maniasis, has been recognized as an opportunistic disease in the immunocompromised, particularly in patients infected with human immunodeficiency virus.
Abstract: Leishmaniasis is a protozoan disease whose diverse clinical manifestations are dependent both on the infecting species of Leishmania and the immune response of the host. Transmission of the disease occurs by the bite of a sand fly infected with Leishmania parasites. Infection may be restricted to the skin in cutaneous leishmaniasis, limited to the mucous membranes in mucosal leishmaniasis, or spread internally in visceral leishmaniasis or kala azar. The overall prevalence of leishmaniasis is 12 million cases worldwide, and the global yearly incidence of all clinical forms approaches 2 million new cases (World Health Organization WHO/LEISH/200.42, Leishmania/HIV Co-Infection in Southwestern Europe 1990–98: Retrospective Analysis of 965 Cases, 2000). In the last two decades, leishmaniasis, especially visceral leishmaniasis, has been recognized as an opportunistic disease in the immunocompromised, particularly in patients infected with human immunodeficiency virus.
TL;DR: These studies provide a promising alternative for protection against leishmaniasis with a switch of CD4+ differentiation from Th2 to Th1, indicative of long-term resistance.
Abstract: The virulence of Leishmania donovani in mammals depends at least in part on cysteine proteases because they play a key role in CD4 + T cell differentiation. A 6-fold increase in NO production was observed with 0.5 μM chicken cystatin, a natural cysteine protease inhibitor, in IFN-γ-activated macrophages. In a 45-day BALB/c mouse model of visceral leishmaniasis, complete elimination of spleen parasite burden was achieved by cystatin in synergistic activation with a suboptimal dose of IFN-γ. In contrast to the case with promastigotes, cystatin and IFN-γ inhibited the growth of amastigotes in macrophages. Although in vitro cystatin treatment of macrophages did not induce any NO generation, significantly enhanced amounts of NO were generated by macrophages of cystatin-treated animals. Their splenocytes secreted soluble factors required for the induction of NO biosynthesis, and the increased NO production was paralleled by a concomitant increase in antileishmanial activity. Moreover, splenocyte supernatants treated with anti-IFN-γ or anti-TNF-α Abs suppressed inducible NO generation, whereas i.v. administration of these anticytokine Abs along with combined therapy reversed protection against infection. mRNA expression and flow cytometric analysis of infected spleen cells suggested that cystatin and IFN-γ treatment, in addition to greatly reducing parasite numbers, resulted in reduced levels of IL-4 but increased levels of IL-12 and inducible NO synthase. Not only was this treatment curative when administered 15 days postinfection, but it also imparted resistance to reinfection. These studies provide a promising alternative for protection against leishmaniasis with a switch of CD4 + differentiation from Th2 to Th1, indicative of long-term resistance.
TL;DR: Generic sodium stibogluconate versus Pentostam under field conditions in Ethiopian patients with visceral leishmaniasis found no significant differences, but HIV-positive patients relapsing with VL could become a reservoir of antimonial-resistant Leishmania donovani.
Abstract: We evaluated generic sodium stibogluconate (SSG) (International Dispensary Association, Amsterdam) versus Pentostam (sodium stibogluconate, GlaxoWellcome, London) under field conditions in Ethiopian patients with visceral leishmaniasis (VL; kala-azar). The 199 patients were randomly assigned to Pentostam (n = 104) or SSG (n = 95) in 1998/99; both drugs were given at 20 mg/kg intra-muscularly for 30 days. A clinical cure after 30-days treatment was achieved in 70.2% (Pentostam) and 81.1% (SSG). There were no significant differences between the 2 drugs for the following parameters: frequency of intercurrent events (vomiting, diarrhoea, bleeding or pneumonia) or main outcome (death during treatment and death after 6-month follow-up; relapse or post kala-azar dermal leishmaniasis at 6-months follow-up). Twenty-seven patients had confirmed co-infection with HIV. On admission, HIV co-infected VL patients were clinically indistinguishable from HIV-negative VL patients. The HIV co-infected VL patients had a higher mortality during treatment (33.3% vs 3.6%). At 6-month follow-up, HIV-positive patients had a higher relapse rate (16.7% vs 1.2%), a higher death rate during the follow-up period (14.3% vs 2.4%), and more frequent moderate or severe post kala-azar dermal leishmaniasis (27.3% vs 13.3%). Only 43.5% of the HIV-positive patients were considered cured at 6-months follow-up vs 92.1% of the HIV-negative patients. HIV-positive patients relapsing with VL could become a reservoir of antimonial-resistant Leishmania donovani.
TL;DR: Spatial analysis of the association between all incidents cases of human Visceral Leishmaniasis and seropositive dogs, from 1994 to 1997 in Belo Horizonte, a large Brazilian city, concluded that human and dog rates are correlated.
Abstract: In this paper, we present spatial analysis of the association between all incidents cases of human Visceral Leishmaniasis and seropositive dogs, from 1994 to 1997 in Belo Horizonte, a large Brazilian city. We geocoded 158 human cases and 11,048 seropositive dogs and compared canine prevalence rates with Human Bayesian Incidence rates in the same areas. We also used Knox's test to evaluate the hypothesis of space-time clustering of human cases in the period. Additionally, we used Kernel's maps for seropositive dogs distribution and located the human cases in the resulting smooth maps. We concluded that human and dog rates are correlated. Also, the Visceral Leishmaniasis in Belo Horizonte spread quickly, but apart from the rates' magnitude, it has kept the same spatial pattern through time. We believe it is possible to use this technique to choose areas to implement control measures against Visceral Leishmaniasis in a more efficient way.
TL;DR: The extremely high levels of anti-rK39 antibodies in VL cases suggest the application of rK 39 for sensitive and specific serodiagnosis, and rK39 ELISA is also valuable in monitoring drug therapy and detecting relapse of the disease.
Abstract: The recombinant product (rK39) of the 39-amino-acid repeats encoded by a kinesin-like protein-encoding gene of Leishmania chagasi was evaluated by enzyme-linked immunosorbent assay (ELISA) for diagnostic potential and the ability to predict the response to therapy in Indian kala-azar or visceral leishmaniasis (VL); we also compared its performance with that of crude soluble antigen (CSA). At the diagnosis of VL, the anti-rK39 antibody titer was 59-fold higher than the anti-CSA antibody titer. With successful therapy, antibody titers declined steeply at the end of treatment and during follow-up. In contrast, patients who relapsed showed increased titers of antibodies to rK39. The extremely high levels of anti-rK39 antibodies in VL cases suggest the application of rK39 for sensitive and specific serodiagnosis, and rK39 ELISA is also valuable in monitoring drug therapy and detecting relapse of the disease.
TL;DR: PCR with peripheral blood is a reliable method for diagnosis of visceral leishmaniasis in HIV-infected patients during follow-up and it substantially reduces the need for traditional invasive tests to assess parasitological response, while a positive PCR result is predictive of clinical relapse.
Abstract: A group of 76 consecutive human immunodeficiency virus (HIV)-positive patients with fever of unknown origin (n = 52) or fever associated with pulmonary diseases was evaluated in order to assess the usefulness of PCR with peripheral blood in the diagnosis and follow-up of visceral leishmaniasis. We identified 10 cases of visceral leishmaniasis among the 52 patients with fever of unknown origin. At the time of diagnosis, all were parasitemic by PCR with peripheral blood. During follow-up, a progressive decline in parasitemia was observed under therapy, and all patients became PCR negative after a median of 5 weeks (range, 6 to 21 weeks). However, in eight of nine patients monitored for a median period of 88 weeks (range, 33 to 110 weeks), visceral leishmaniasis relapsed, with positive results by PCR with peripheral blood reappearing 1 to 2 weeks before the clinical onset of disease. Eight Leishmania infantum and two Leishmania donovani infections were identified by PCR-restriction fragment length polymorphism analysis. PCR with peripheral blood is a reliable method for diagnosis of visceral leishmaniasis in HIV-infected patients. During follow-up, it substantially reduces the need for traditional invasive tests to assess parasitological response, while a positive PCR result is predictive of clinical relapse.
TL;DR: Alum-precipitated ALM+BCG is suggested as a potential vaccine against visceral leishmaniasis and warrants clinical trials, indicating IFN-gamma response as a sensitive parameter of immune status.
TL;DR: Dogs are the domestic reservoir for Leishmania infantum, the parasite causing zoonotic visceral leishmaniasis in both the Old and New Worlds, and the development of a canine Leishmanniasis vaccine is highly desirable.
01 Jan 2001
TL;DR: Em fevereiro of 2001, as modificações propostas foram apresentadas para os representantes das secretarias estaduais de saúde e das coordenaçãoes regionais da Fundação Nacional de Saúde, para implementaçao.
Abstract: Endereço para correspondência: Dr. Carlos Henrique Nery Costa. Laboratório de Leishmanioses/Hospital de Doenças Infecto-Contagiosas. R. Gov. Artur de Vasconcelos 151-Sul, 64000-450 Teresina, PI, Brasil. Tel: 55 86 221-3413 Fax: 55 86 221-2424 e-mail: crlshncst@aol.com Recebido em 23/2/2001 Depois de duas décadas de tentativas de controle da leishmaniose visceral (LV) no Brasil, o número de casos no país aumentou nitidamente e invadiu áreas urbanas, onde encontrou-se com a AIDS27. A recente proposta do Ministério da Saúde de reavaliar os programas de controle de endemias, aliada ao reconhecimento da pouca eficiência do programa brasileiro para LV, levou à convocação de um comitê de consultores para analisar o programa atual e propor mudanças para o controle da doença no país. Foram realizadas algumas reuniões do grupo técnico, a última tendo ocorrido em 4 de dezembro de 2000 em Brasília. Esta reunião contou com a presença dos consultores da Ministerio da Saúde e Técnico da Fundação Nacional de Saúde: Almério de Castro Gomes (Universidade de São Paulo), Carlos Henrique Nery Costa ( Universidade Federal do Piauí), Jackson Mauricio Lopes Costa (Universidade Federal do Maranhão), João Batista Furtado Vieira (Fundação Nacional de Saúde), José Wellington de Oliveira Lima (Fundação Nacional de Saúde) e Reinaldo Dietze (Universidade Federal do Espírito Santo). Em fevereiro de 2001, as modificações propostas foram apresentadas para os representantes das secretarias estaduais de saúde e das coordenações regionais da Fundação Nacional de Saúde, para implementação. O programa brasileiro, iniciado há mais de 40 anos, é composto pela integração de três medidas de saúde pública: a distribuição gratuita do tratamento específico, o controle de reservatórios domésticos e o controle de vetores. A medicação distribuída nas unidades públicas de saúde onde se trata LV são compostos de antimônio pentavalente, com dose recomendada de 20mg/kg/dia por no mínimo 20 dias. O controle de reservatórios tem sido feito através do diagnóstico sorológico de todos os cães domésticos onde existe transmissão de Leishmania chagasi para seres humanos. Para isto, foi estruturada uma rede de testes de imunofluorescência, utilizando-se eluato de papel de filtro; todos os cães com resultado reagente têm sido sacrificados. Finalmente, o controle do vetor, essencialmente para o flebótomo Lutzomyia longipalpis, é aplicado eventualmente com o uso de inseticidas, por After two decades of efforts to control visceral leishmaniasis (VL) in Brazil, the nation’s number of cases have had a distinct increase, and invaded cities where VL met AIDS 27. The recent proposition of the Ministry of Health to evaluate the programs of control of endemic diseases and the recognition of the poor performance of the Brazilian program for VL, led to the calling of a committee of advisers. They were asked to analyze the present program and to suggest changes for the control of the disease in the country. Some meetings took place in the year 2,000, the last in the 4 th of December. The following advisers attended this last meeting: the Counselor of the Ministerio da Saúde e Technician of the Fundação Nacional de Saeude: Almério de Castro Gomes (Universidade de São Paulo), Carlos Henrique Nery Costa ( Universidade Federal do Piauí), Jackson Mauricio Lopes Costa (Universidade Federal do Maranhão), João Batista Furtado Vieira (Fundação Nacional de Saúde), José Wellington de Oliveira Lima (Fundação Nacional de Saúde) e Reinaldo Dietze (Universidade Federal do Espírito Santo). In February of 2001, the proposed changes were presented to the regional offices of Fundação Nacional de Saúde and to the state health offices, for implementation.
TL;DR: The main topics concerning the epidemiology, clinical presentation and therapy of AIDS-related VL are reviewed.
TL;DR: Post kala-azar dermal leish maniasis (PKDL) is increasingly recognized in Sudan as a complication of visceral leishmaniasis (VL), occurring in c .
Abstract: Post kala-azar dermal leishmaniasis (PKDL) is increasingly recognized in Sudan as a complication of visceral leishmaniasis (VL), occurring in c. 55% of patients after, or during treatment of, VL. The development of PKDL seems to be restricted to parasites of the Leishmania donovani sensu stricto cluster; no particular zymodeme has been found to be associated with it. In contrast to PKDL in India, PKDL in Sudan occurs within 0-6 months after treatment for VL. The rash may be macular, maculo-papular or nodular, and spreads from the perioral area to other parts of the body, depending on grade of severity. Young children are particularly at risk of developing more severe disease. In 16% of PKDL patients, parasites can be demonstrated by microscopy in lymph node or bone marrow aspirates and, with the aid of the polymerase chain reaction (PCR), in lymph nodes of 81% of patients, possibly indicating persistent visceralized infection. Diagnosis can be made by demonstration of parasites in skin smears or biopsies in 20-30% of cases; newer techniques, using PCR with skin smears, have higher sensitivity (83%). Monoclonal antibodies against L. donovani can detect parasites in 88% of biopsies. Serological tests are of limited value. The leishmanin skin test is positive in 50-60% of cases; there is an inverse relationship between the skin test result and severity of PKDL. In differential diagnosis, miliaria rubra is the most common problem; differentiation from leprosy is the most difficult. In biopsies, hyperkeratosis, parakeratosis, acanthosis, follicular plugging and liquefaction degeneration of the basal layer may be found in the epidermis; in the dermis there are varying intensities of inflammation with scanty parasites and mainly lymphocytes; macrophages and epithelioid cells may also be found. In 20% of cases discrete granulomas may be found. After VL, the immune response shifts from a Th2-type to a mixed Th1/Th2-type. High levels of interleukin-10 in skin biopsies as well as in peripheral blood mononuclear cells and plasma in patients with VL predict the development of PKDL. Treatment is needed only for those who have severe and prolonged disease; sodium stibogluconate (20 mg/kg/d for 2 months) is usually sufficient. (Liposomal) amphotericin B is effective, whereas ketoconazole, terbinafine and itraconazole are not.