Showing papers on "Visceral leishmaniasis published in 1999"
TL;DR: The following discussion of the data submitted in support of the New Drug Application for AmBisome shows the breadth of data from clinical trials that can be appropriate to support approval for drugs to treat tropical diseases.
Abstract: In August 1997, AmBisome (liposomal amphotericin B, Nexstar, San Dimas, CA) was the first drug approved for the treatment of visceral leishmaniasis by the U.S. Food and Drug Administration. The growing recognition of emerging and reemerging infections warrants that safe and effective agents to treat such infections be readily available in the United States. The following discussion of the data submitted in support of the New Drug Application for AmBisome for the treatment of visceral leishmaniasis shows the breadth of data from clinical trials that can be appropriate to support approval for drugs to treat tropical diseases.
256 citations
Journal Article•
TL;DR: Until a safe and effective vaccine is developed, a combination of sandfly control, detection and treatment of patients and prevention of drug resistance is the best approach for controlling kala-azar.
Abstract: Kala-azar has re-emerged from near eradication. The annual estimate for the incidence and prevalence of kala-azar cases worldwide is 0.5 million and 2.5 million, respectively. Of these, 90% of the confirmed cases occur in India, Nepal, Bangladesh and Sudan. In India, it is a serious problem in Bihar, West Bengal and eastern Uttar Pradesh where there is under-reporting of kala-azar and post kala-azar dermal leishmaniasis in women and children 0-9 years of age. Untreated cases of kala-azar are associated with up to 90% mortality, which with treatment reduces to 15% and is 3.4% even in specialized hospitals. It is also associated with up to 20% subclinical infection. Spraying of DDT helped control kala-azar; however, there are reports of the vector Phlebotomus argentipes developing resistance. Also lymphadenopathy, a major presenting feature in India raises the possibility of a new vector or a variant of the disease. The widespread co-existence of malaria and kala-azar in Bihar may lead to a difficulty in diagnosis and inappropriate treatment. In addition, reports of the organism developing resistance to sodium antimony gluconate--the main drug for treatment--would make its eradication difficult. Clinical trials in India have reported encouraging results with amphotericin B (recommended as a third-line drug by the National Malaria Eradication Programme). Phase III Trials with a first-generation vaccine (killed Leishmania organism mixed with a low concentration of BCG as an adjuvant) have also yielded promising results. Preliminary studies using autoclaved Leishmania major mixed with BCG have been successful in preventing infection with Leishmania donovani. Until a safe and effective vaccine is developed, a combination of sandfly control, detection and treatment of patients and prevention of drug resistance is the best approach for controlling kala-azar.
251 citations
TL;DR: The medical records of 158 dogs with visceral leishmaniasis confirmed cytologically and/or serologically and clinicopathological abnormalities were reviewed, and an indirect immunofluorescence assay's diagnostic sensitivity was found to be higher than that of lymph node aspiration cytology.
Abstract: The medical records of 158 dogs with visceral leishmaniasis confirmed cytologically and/or serologically were reviewed. Ages of affected dogs varied from nine months to 15 years, with a male-to-female ratio of 1.3. The most common clinical manifestations of the disease were variable cutaneous lesions such as exfoliative dermatitis and skin ulcerations, chronic renal failure, peripheral lymphadenopathy or lymph node hypoplasia, masticatory muscle atrophy (i.e., chronic myositis), ocular lesions (i.e., conjunctivitis, keratoconjunctivitis sicca, blepharitis, and uveitis), and poor body condition. Ascites, nephrotic syndrome, epistaxis, polyarthritis, and ulcerative stomatitis were seen only in a small number of cases. Clinical splenomegaly was not a common finding. The clinicopathological abnormalities were nonregenerative anemia, hyperproteinemia, glomerular proteinuria, and symptomatic or asymptomatic azotemia. In this study, an indirect immunofluorescence assay's diagnostic sensitivity was found to be higher than that of lymph node aspiration cytology.
248 citations
TL;DR: Visceral leishmaniasis has to be considered in children with fever, pancytopenia, and splenomegaly, even if the child has not been to an endemic area and even if there is no evidence of the disease in his environment.
Abstract: In this article, we report the case of a 16-month-old German boy who was admitted to the Children's Hospital of Stuttgart with a 4-week history of intermittent fever, decreased appetite, weakness, fatigue, and difficulty sleeping. He was healthy at birth and remained so for the first 15 months of his life. On admission, physical examination showed enlarged cervical, axillary, and inguinal lymph nodes, as well as hepatosplenomegaly. Laboratory data revealed pancytopenia, elevated liver function tests, and hypergammaglobulinemia. Blood, stool, and urine culture results were negative. Viral infections and rheumatologic and autoimmune disorders were ruled out, but a positive titer for Leishmania antibodies was noted. In a liver and bone marrow biopsy, the amastigote form of the parasite could not be seen in cells. The promastigote form of Leishmania was found and the diagnosis of visceral leishmaniasis was made by combining the cultures of both the liver and the bone marrow biopsy material in 5 mL 0.9% saline on brain heart infusion agar, supplemented with defibrinated rabbit blood and incubated at 25 to 26 degrees C for 5 days. The parasite was identified by Southern blot analysis as Leishmania infantum. Specific therapy with the antimonial compound sodium stibogluconate with a dose of 20 mg/kg body weight was begun immediately. Within 4 days, the patient became afebrile. The side effects of treatment, including erosive gastritis, cholelithiasis, worsening hepatosplenomegaly, elevation of liver enzymes, pancreatitis, and electrocardiogram abnormalities, necessitated the discontinuation of treatment after 17 days. On discharge 4 weeks later, the patient was stabilized and afebrile with a normal spleen, normal complete blood count, normal gammaglobulins, and decreasing antibody titers to Leishmania. During the next 24 months, the patient experienced intermittent episodes of abdominal pain, decreased appetite, recurrent arthralgia, and myalgia. But at his last examination in January 1998, he was well; all symptoms mentioned above had disappeared. Because the child had never left Germany, nonvector transmission was suspected and household contacts were examined. His mother was the only one who had a positive antibody titer against Leishmania donovani complex. She had traveled several times to endemic Mediterranean areas (Portugal, Malta, and Corse) before giving birth to the boy. But she had never been symptomatic for visceral leishmaniasis. Her bone marrow, spleen, and liver biopsy results were within normal limits. Culture results and polymerase chain reaction of this material were negative. A Montenegro skin test result was positive, indicating a previous infection with Leishmania. Western blot analysis showed specific recognition by maternal antibodies of antigens of Leishmania cultured from the boy's tissue. Visceral leishmaniasis is endemic to several tropical and subtropical countries, but also to the Mediterranean region. It is transmitted by the sand fly (Phlebotomus, Lutzomyia). Occasional nonvector transmissions also have been reported through blood transfusions, sexual intercourse, organ transplants, excrements of dogs, and sporadically outside endemic areas. Only 8 cases of congenital acquired disease have been described before 1995, when our case occurred. In our patient, additional evaluation showed that the asymptomatic mother must have had a subclinical infection with Leishmania that was reactivated by pregnancy, and then congenitally transmitted to the child. Visceral leishmaniasis has to be considered in children with fever, pancytopenia, and splenomegaly, even if the child has not been to an endemic area and even if there is no evidence of the disease in his environment, because leishmaniasis can be transmitted congenitally from an asymptomatic mother to her child.
134 citations
TL;DR: Treatment of VL with meglumine antimoniate or amphotericin B was shown to have similar efficacy and toxicity rates in Spanish HIV-infected patients, and the differences in the toxicity patterns could be useful in choosing one of these agents as first-line treatment.
Abstract: BACKGROUND Visceral leishmaniasis is common in patients with HIV infection living in endemic areas, but the most effective and safe treatment remains unknown. OBJECTIVE To compare the efficacy and safety of meglumine antimoniate versus amphotericin B in HIV-infected patients with first episodes of visceral leishmaniasis (VL). DESIGN An open, multicentre, prospective and randomized trial. SETTING Twelve tertiary hospitals. PATIENTS Eighty-nine consecutive HIV-infected patients diagnosed with VL. Patients were randomly assigned to treatment with either meglumine antimoniate (20 mg pentavalent antimony per kilogram of body weight per day) or amphotericin B (0.7 mg/kg per day) both for 28 days. Treatment was considered successful if a bone marrow aspirate performed 1 month after the end of therapy did not detect parasites. Relapse was defined as the reappearance of parasites after an initial cure. RESULTS An initial cure was attained in 29 of 44 patients (65.9%) randomly assigned to treatment with meglumine antimoniate and 28 of 45 (62.2%) randomly assigned to treatment with amphotericin B. The incidence of moderate to severe adverse events was similar in both groups. The patients treated with meglumine antimoniate had higher incidences of cardiotoxicity (14 versus 0%, P = 0.02) and chemical pancreatitis (30 versus 0%, P < 0.01). However, in the amphotericin B group, nephrotoxicity was more frequent (36 versus 5%, P < 0.01). There was no difference in survival or relapse-free interval according to the allocated group of therapy. CONCLUSION Treatment of VL with meglumine antimoniate or amphotericin B was shown to have similar efficacy and toxicity rates in Spanish HIV-infected patients. The differences in the toxicity patterns could be useful in choosing one of these agents as first-line treatment.
120 citations
TL;DR: Data show that L. donovani susceptibility to SbV is parasite intrinsic, stage specific, and macrophage independent, indicating cross-resistance to S bV-containing compounds.
Abstract: The standard treatment of human visceral leishmaniasis involves the use of pentavalent antimony (SbV) compounds. In recent years increasing numbers of clinical failures of treatment with SbV have been reported, probably due to the development of parasite resistance to this compound. The mode of action and mechanisms of resistance to SbV have not been fully elucidated. In the present study an axenic amastigote culture was used to study the in vitro responses of Leishmania donovani to SbV. Susceptibility to both sodium stibogluconate and meglumine antimoniate was found to be stage specific. Amastigotes were 73 to 271 times more susceptible to SbV than were promastigotes. As opposed to SbV, trivalent antimony (SbIII) was similarly toxic to both developmental stages. When promastigotes were transformed to amastigotes, susceptibility to meglumine antimoniate developed after 4 to 5 days, upon the completion of differentiation. In contrast, with transformation from amastigotes to promastigotes, resistance to meglumine antimoniate was acquired rapidly, within 24 h, before the completion of differentiation. The culture of promastigotes at an acidic pH (5.5) or at an elevated temperature (37°C) alone did not lead to the appearance of SbV susceptibility, emphasizing the requirement of both these environmental factors for the development of SbV susceptibility. A previously isolated sodium stibogluconate (Pentostam)-resistant L. donovani mutant (Ld1S.20) is also resistant to meglumine antimoniate, indicating cross-resistance to SbV-containing compounds. In contrast, no cross-resistance was found with SbIII, suggesting a mechanism of SbV resistance different from that described in Leishmania tarentolae. These data show that L. donovani susceptibility to SbV is parasite intrinsic, stage specific, and macrophage independent.
120 citations
TL;DR: Peripheral blood mononuclear cell subsets, in vitro lymphoproliferative response to leishmanial antigen, and Leishmania-specific serum antibody levels were examined in 11 dogs, naturally infected with L. infantum, and 9 healthy control dogs and levels returned to those observed during CVL.
108 citations
TL;DR: The clinical picture is dependent on determinants related to the infecting species of Leishmania and the host, including infectivity, virulence of the parasite, extent of lymphatic and hematogenous spread in addition to immune response, and genetic susceptibility of the host.
107 citations
TL;DR: In this article, a 1 year prospective survey was carried out on 5671 people in a Leishmania infantum focus in north-west Iran, and the average incidence rate of infection since 1985 was 2.8%/year with all ages equally at risk.
Abstract: In order to investigate the phenomenon of age-related immunity to visceral leishmaniasis, a 1 year prospective survey was carried out on 5671 people in a Leishmania infantum focus in north-west Iran. The average incidence rate of infection since 1985 was 2.8%/year with all ages equally at risk. One in 13 infections in children led to visceral leishmaniasis (VL), and this ratio decreased significantly with age. Seroprevalence also dropped rapidly with age, suggesting that the same process may affect both clinical outcome and the humoral immune responses. Cell-mediated immunity was associated with a reduction in the seroconversion rate and an increase in the serorecovery rate. Even amongst people with no detectable cell-mediated immunity to Leishmania, the seroconversion rate decreased and the serorecovery rate increased with age. All current VL patients had a negative leishmanin skin test response. Hence, adults may develop protection against L. infantum through 2 processes, 1 dependent and 1 independent of acquired cell-mediated immunity.
96 citations
TL;DR: Evidence is provided for the existence of a Th1/Th2 dichotomy in the T-cell response to Leishmania antigens in human leishmaniasis and the data suggest that the pattern of IL-4 and IFN-gamma response is polarised in these patients.
95 citations
TL;DR: Although there is an apparent lack of clinical symptoms in these dogs, asymptomatic animals harbor a chronic L. infantum infection and as such consist a ‘dangerous’ reservoir with regard to the spread of the disease.
Abstract: Leishmania (L.) infantum is the etiological agent of human and canine visceral leishmaniasis in the Mediterranean subregion. Domestic dogs are the main reservoir of the parasite in most urban areas. A survey of 1638 asymptomatic dogs registered in Greater Athens area was carried out in the Hellenic Pasteur Institute during the period 1986-1994 to investigate the prevalence of canine visceral leishmaniasis in apparently healthy dogs. Dog sera was tested using the indirect fluorescent antibody technique (IFAT). Of the 1638 dogs, 366 (22.4%) had anti-Leishmania infantum antibodies at titre greater than or equal to 1/200 which were considered positive; 53 (3.2%) had antibody titres of 1/100 and were considered uncertain; and 1219 (74.4%) dogs were seronegative. From the 366 seropositive dogs, 212 were positive at 1/1600 serum dilution, 57 at 1/800, 38 at 1/400 and 59 at 1/200. The results were plotted according the site of residence, breed and age. The rate of asymptomatic infections with L. infantum dogs in Greater Athens area appears to be significantly high. Although there is an apparent lack of clinical symptoms in these dogs, asymptomatic animals harbor a chronic L. infantum infection and as such consist a 'dangerous' reservoir with regard to the spread of the disease.
TL;DR: The bias generated by commonly used test validation procedures was examined and any operational guideline on DAT use has to consider the critical dependency of the predictive values of the test on VL prevalence rates.
Abstract: The validity of the direct agglutination test (DAT) for visceral leishmaniasis (VL) was studied with a standardized field kit on 148 clinically suspected persons and 176 healthy controls recruited between 1993 and 1994 from an endemic area in Gedaref State, Sudan. A sensitivity of 95.9% and a specificity of 99.4% were found at a 1: 8,000 cut-off titer when parasitologically confirmed cases were compared with healthy controls. While corroborating previously reported sensitivity and specificity estimates of this serodiagnostic test, this study examined the bias generated by commonly used test validation procedures. The fundamental methodologic problem in VL test validation is the absence of a reliable gold standard. Moreover, any operational guideline on DAT use has to consider the critical dependency of the predictive values of the test on VL prevalence rates. The DAT diagnostic cut-off titer depends upon many external factors, among which the prevalence of disease in the area and the case mix seem the most important.
TL;DR: Results point to CD8+ T cells and to IL-5- and IFN-γ-producing CD4+ Tcells as possible contributors to human resistance to Leishmania infection and to new immunological approaches in the control of this disease.
Abstract: Visceral leishmaniasis (VL) is a disease caused by the intracellular parasite Leishmania donovani (L. donovani donovani, L. donovani infantum, and L. donovani chagasi), characterized by fever, hepatosplenomegaly and anemia; if left untreated, the disease is lethal within weeks or months. Most studies to identify the immunological factors that determine visceral disease were performed with samples from cured patients (4). In regions where VL is endemic, such as the Mediterranean area, severe disease occurs only in certain subjects whereas a majority of infected individuals show no clinical symptoms (2, 18); previous infections in asymptomatic subjects can be demonstrated by immunological means: skin tests performed with Leishmania lysates are positive and partially correlate with detection of specific antibodies (Abs) by Western blot analysis, and blastogenesis assays using peripheral blood mononuclear cells (PBMC) show a T-cell proliferative response (16, 17). These results indicate a persistent immune response in such individuals. The immunological mechanisms that control parasite multiplication in asymptomatic subjects are not well defined.
Experimental models indicate that parasite-specific CD4+ Th1 cells are critical for the control of primary infection by C57BL/6 mice infected with L. major (26), whereas control of infection by BALB/c infected with L. donovani has been partially associated with the expansion of parasite-specific CD8+ lymphocytes (29).
The aim of the present work was to characterize at the single-cell level the parasite-specific T-lymphocyte response in asymptomatic subjects who spontaneously control the infection by comparison to VL patients who control the infection after chemotherapy. To this end, we derived Leishmania-specific T-cell clones (TCC) from the blood T lymphocytes and analyzed their phenotypes. The results of this analysis strongly suggest a role of CD8+ T cells in the control of infection in asymptomatic subjects. It also uncovers a new CD4+ T-cell subpopulation producing large amounts of both gamma interferon (IFN-γ) and interleukin-5 (IL-5).
TL;DR: It is suggested that pre-treatment HIV viral load influences response to anti-leishmanial chemotherapy and active VL is associated with increased viral replication in vivo, supporting the notion that dual infection plays an important role in the pathogenesis and disease progression of either infection.
Abstract: Objective: To investigate whether clearance of Leishmania parasites from tissue aspirate smears in patients with HIV and visceral leishmaniasis (VL) co-infection treated with pentavalent antimonials is influenced by initial HIV viral load and to assess the effect of active VL on HIV viral load and replication in vivo. Methods: Leishmania parasites were identified in Giemsa-stained smears prepared from tissue aspirates. Parasite index was determined by quantifying Leishmania donovani bodies in smears. HIV-1 RNA was quantitated by using the nucleic acid sequence-based amplification technique with a limit of detection of 500 copies/ml. All patients were treated with pentavalent antimonials at 20 mg pentavalent antimony (Sb v )/kg daily for a total of 28 days. None of the patients received specific anti-retroviral therapy. Results: Seventeen patients (73.9%) showed good initial response to anti-leishmanial treatment and the remaining six (26.1%) had very poor response. Among the good responders, 11 (64.7%) had no demonstrable Leishmania donovani bodies in post-therapy tissue aspirate smear preparations, and in the remaining six (35.3%) their parasite loads were reduced to very low levels. Patients with poor response had persistently high parasite index despite completion of anti-leishmanial chemotherapy. Poor responders had pre-treatment median HIV viral load that was > 160-fold higher than responders to anti-leishmanial chemotherapy; [410 000 copies/ml (quartile range, 33 000-530 000) and 2500 copies/ml (quartile range 500-297 500), respectively]. Furthermore, compared with pre-treatment viral concentrations, patients with good response showed marked reduction in post-treatment viral load. In contrast, post-treatment HIV viral concentrations were markedly increased among patients with poor response to anti-leishmanial therapy. Conclusions: The results suggest that pre-treatment HIV viral load influences response to anti-leishmanial chemotherapy and active VL is associated with increased viral replication in vivo, supporting the notion that dual infection plays an important role in the pathogenesis and disease progression of either infection.
TL;DR: The dosing regimen of MA currently recommended for treating VL is associated with a high rate of serious side effects in HIV-1-infected patients, and treatment with MA was permanently discontinued due to serious adverse effects that included acute pancreatitis, acute renal failure, and leukopenia.
Abstract: Organic pentavalent antimonials are one of the mainstays of treatment for visceral leishmaniasis (VL). Few data are available on the toxicity and efficacy of these drugs at the dosing schedule recommended by the Centers for Disease Control and Prevention (CDC) (Atlanta, GA). We analyzed 25 VL episodes in human immunodeficiency virus (HIV)-infected patients who were treated with meglumine antimoniate (MA) at the CDC-recommended dose in southern Spain. Adverse effects were observed in 14 (56%) VL episodes. In 7 (28%), treatment with MA was permanently discontinued due to serious adverse effects that included acute pancreatitis, acute renal failure, and leukopenia. Three (12%) patients died during therapy due to severe acute pancreatitis attributable to MA. The dosing regimen of MA currently recommended for treating VL is associated with a high rate of serious side effects in HIV-1-infected patients.
TL;DR: Very good activity of SCH 56592 is indicated against cutaneous leishmaniasis due to L. amazonensis infection and, to a lesser degree, against visceral leish maniasis dueto L. donovani infection in susceptible BALB/c mice.
Abstract: Current therapy for leishmaniasis is unsatisfactory. Efficacious and safe oral therapy would be ideal. We examined the efficacy of SCH 56592, an investigational triazole antifungal agent, against cutaneous infection with Leishmania amazonensis and visceral infection with Leishmania donovani in BALB/c mice. Mice were infected in the ear pinna and tail with L. amazonensis promastigotes and were treated with oral SCH 56592 or intraperitoneal amphotericin B for 21 days. At doses of 60 and 30 mg/kg/day, SCH 56592 was highly efficacious in treating cutaneous disease, and at a dose of 60 mg/kg/day, it was superior to amphotericin B at a dose of 1 mg/kg/day. The means of tail lesion sizes were 0.32 ± 0.12, 0.11 ± 0.06, 0.17 ± 0.07, and 0.19 ± 0.08 mm for controls, SCH 56592 at 60 and 30 mg/kg/day, and amphotericin B recipients, respectively (P = 0.0003, 0.005, and 0.01, respectively). Parasite burden in draining lymph nodes confirmed these efficacy findings. In visceral leishmaniasis due to L. donovani infection, mice treated with SCH 56592 showed a 0.5- to 1-log-unit reduction in parasite burdens in the liver and the spleen compared to untreated mice. Amphotericin B at 1 mg/kg/day was superior to SCH 56592 in the treatment of visceral infection, with a 2-log-unit reduction in parasite burdens in both the liver and spleen. These studies indicate very good activity of SCH 56592 against cutaneous leishmaniasis due to L. amazonensis infection and, to a lesser degree, against visceral leishmaniasis due to L. donovani infection in susceptible BALB/c mice.
TL;DR: The results indicate that PKDL develops as a result of an influx of immunocompetent cells into skin, which harbours parasites, and the inflammatory response to the parasites is complex.
Abstract: In Sudan, post kala-azar dermal leishmaniasis (PKDL) caused by Leishmania donovani develops in half of the patients treated for visceral leishmaniasis (kala-azar). In most patients lesions heal spontaneously, but in others symptoms are severe and persist for years. This study examined the immunological response in lesions of PKDL patients by immunohistochemistry and compared the findings with results obtained using peripheral blood mononuclear cells (PBMCs). In all lesions, parasites or parasite antigen were present and provoked the formation of an inflammatory infiltrate consisting of a mixture of macrophages, lymphocytes, and plasma cells. In patients who had high interferon-gamma (IFNgamma) responses to Leishmania antigen in vitro, compact epithelioid granulomas were formed. The inflammatory cells were mainly CD3(+) and interleukin-10 (IL10) was the most prominent cytokine in the lesions. However, IFNgamma was found in all and IL4 in most lesions, in varying amounts. PBMCs from all patients responded to Leishmania antigen by IFNgamma production or proliferation. The results indicate that PKDL develops as a result of an influx of immunocompetent cells into skin, which harbours parasites. The inflammatory response to the parasites is complex. It involves several cell types and cytokines, of which some are antagonistic. It is conceivable that the balance between these cytokines determines the outcome of the disease.
TL;DR: Direct xenodiagnosis of VL was applied to test the infectivity of six coinfected patients to colonized Phlebotomus perniciosus and found that patients who had still not received specific treatment for VL proved to be infective for the sand flies.
Abstract: To determine the role that Leishmania infantum/human immunodeficiency virus (HIV) coinfected patients could play in the epidemiology of visceral leishmaniasis (VL), we applied direct xenodiagnosis of VL in this study to test the infectivity of six coinfected patients to colonized Phlebotomus perniciosus. All patients proved to be infective for the sand flies. The infectivity of patients who had still not received specific treatment for VL was inversely proportional to their absolute CD4+ T lymphocyte cell count. It has been proven that P. perniciosus can acquire and allow the development of L. infantum by feeding on L. infantum/HIV coinfected patients. Since this sand fly is an important vector of VL in southern Europe, a new natural anthroponotic cycle could be considered in the epidemiology of L. infantum/HIV coinfection. The design of leishmaniasis control programs and the management of coinfected individuals should take these findings into account.
TL;DR: The clinical features, treatments, and outcomes of 26 previously reported cases are reviewed, pointing out the lower cure rate associated with human immunodeficiency virus infection.
Abstract: Visceral leishmaniasis is an infectious disease that occurs only rarely in recipients of solid organ grafts but is associated with an elevated mortality rate despite proper treatment. We report five cases diagnosed in our hospital. All the patients were men aged 30 to 60 years who had undergone kidney transplantation (3 patients), heart transplantation (1), or liver transplantation (1). Three of the patients died, one had multiple recurrences, and one developed post-kala-azar cutaneous leishmaniasis. We review the clinical features, treatments, and outcomes of 26 previously reported cases, pointing out the lower cure rate associated with human immunodeficiency virus infection.
TL;DR: Two HIV infected patients with visceral leishmaniasis and unusual cutaneous lesions are described and Leishmania parasites were present in a skin biopsy of a fibrous histiocytoma.
Abstract: Two HIV infected patients with visceral leishmaniasis and unusual cutaneous lesions are described. The first patient developed linear brown macules containing Leishmania parasites on the fingers and palms of the hands. This patient never received highly active antiretroviral treatment and the visceral leishmaniasis could not be cured even with liposomal amphotericin. In the second patient, Leishmania parasites were present in a skin biopsy of a fibrous histiocytoma. After completing visceral leishmaniasis treatment, a discrete elevation of one of his tattoos was seen. A biopsy specimen of this tattoo revealed Leishmania amastigotes. In this patient the visceral leishmaniasis was finally cured with meglumine antimoniate, followed by pentacarinat isothianate as maintenance therapy in conjunction with highly active antiretroviral treatment.
TL;DR: Analysis of mRNA levels of infected spleen cells suggested that targeted drug treatment together with IFN-gamma, in addition to greatly reducing parasite numbers, resulted in reduced levels of interleukin (IL)-4 but increased levels of IL-12 and inducible nitric oxide synthase.
Abstract: Active targeting of doxorubicin to macrophages was studied by incorporating it in mannose-coated liposomes by use of visceral leishmaniasis in BALB/c mice as the model macrophage disease. Mannosylated liposomal doxorubicin was more effective than liposomal doxorubicin or free doxorubicin. Because leishmaniasis is accompanied by immunosuppression, immunostimulation by interferon (IFN)-gamma was evaluated to act synergistically with mannosylated liposomal doxorubicin therapy. Combination chemotherapy with a suboptimal dose of IFN-gamma resulted in possibly complete elimination of spleen parasite burden. Analysis of mRNA levels of infected spleen cells suggested that targeted drug treatment together with IFN-gamma, in addition to greatly reducing parasite numbers, resulted in reduced levels of interleukin (IL)-4 but increased levels of IL-12 and inducible nitric oxide synthase. Such combination chemotherapy may provide a promising alternative for the cure of leishmaniasis, with a plausible conversion of antiparasitic T cell response from a Th2 to Th1 pattern indicative of long-term resistance.
TL;DR: It was shown that certain tribes from northern Sudan were more likely to develop subclinical infections, while those of the Baria tribe from southern Sudan and the Nuba tribe from western Sudan wereMore likely to development visceral leishmaniasis.
Abstract: In 1994-1996, we studied a group of 58 game wardens stationed in an area known to be highly endemic for visceral leishmaniasis (kala-azar) for evidence of infection with Leishmania donovani. Leishmania DNA was detected by the polymerase chain reaction in the peripheral blood of cases of active kala-azar, former patients with visceral leishmaniasis, patients, and asymptomatic subjects. Using the cloned antigen rk39, antibodies were detected in 44.2% of the game wardens while leishmanin skin test result was positive in 77% of our sample. It was shown that certain tribes from northern Sudan were more likely to develop subclinical infections, while those of the Baria tribe from southern Sudan and those of the Nuba tribe from western Sudan were more likely to develop visceral leishmaniasis. Whether this is due to genetic factors or previous exposure to Leishmania parasites remains to be elucidated.
TL;DR: There are major programs for the elimination of tuberculosis, leprosy, and malaria, and to control brucellosis, leishmaniasis, sexually transmitted diseases, trachoma, acute respiratory infection in children, and diarrheal diseases.
Abstract: Oman is generally hot and dry, but the Salalah region in southern Dhofar province is relatively cool and rainy during the summer monsoon, and has a distinctive pattern of infection. Important, notifiable infections in Oman include tuberculosis, brucellosis (endemic in Dhofar), acute gastroenteritis, and viral hepatitis: 4.9% of the adults are seropositive for hepatitis B surface antigen and approximately 1.2% for hepatitis C virus. Infection with human immunodeficiency virus is uncommon, and leprosy, rabies, and Crimean-Congo hemorrhagic fever are rare. Between 1990 and 1998, the incidence of malaria, (>70% due to Plasmodium falciparum) decreased from 32,700 to 882 cases. Cutaneous and visceral leishmaniasis (caused by Leishmania tropica and L. infantum, respectively) and Bancroftian filariasis occur sporadically. Intestinal parasitism ranges from 17% to 42% in different populations. A solitary focus of schistosomiasis mansoni in Dhofar has been eradicated. There are major programs for the elimination of tuberculosis, leprosy, and malaria, and to control brucellosis, leishmaniasis, sexually transmitted diseases, trachoma, acute respiratory infection in children, and diarrheal diseases. The Expanded Program on Immunization was introduced in 1981: diphtheria, neonatal tetanus, and probably poliomyelitis have been eliminated.
TL;DR: Results indicate that ACL is more prevalent than previously thought, affecting up to 10% of a local population, and the fact that the same parasite appears to cause both ACL and the potentially fatal visceral disease suggests that the host immune response is critical in determining the outcome of L. chagasi infection.
Abstract: Leishmania chagasi, the causative agent of visceral leishmaniasis (VL) in the Americas, has recently been associated with atypical cutaneous leishmaniasis (ACL) in Central America; however, little comprehensive information about this disease is available. Clinical, epidemiologic, and parasitologic characteristics of 252 ACL cases and 44 VL cases in Nicaragua were analyzed. Visceral leishmaniasis is primarily associated with malnourished children less than five years of age, whereas ACL is found predominantly in children greater than five years of age and young adults. Genetically similar parasites are associated with both disease manifestations. The sand fly Lutzomyia evansi, in addition to Lu. longipalpis, may be involved in transmission of L. chagasi to humans. Our results indicate that ACL is more prevalent than previously thought, affecting up to 10% of a local population. The fact that the same parasite appears to cause both ACL and the potentially fatal visceral disease suggests that the host immune response is critical in determining the outcome of L. chagasi infection. The public health implications of the wide-spread presence of L. chagasi are discussed.
TL;DR: Topical treatment with HePC (Miltex) was highly effective in reducing parasite burden and healed established lesions, and the clinical application of Miltex for treatment of cutaneous leishmaniasis may be highly efficient because humans, similarly to resistant mice, in general do not relapse after healing.
Abstract: Ether-lipids and alkylphosphocholines have been found to have anti-leishmanial activity. Oral treatment with hexadecylphosphocholine (HePC) efficiently reduces parasite burden in murine visceral leishmaniasis. Drugs for the treatment of cutaneous leishmaniasis are most commonly administered parenterally, whereas efficient drugs for topical treatment are not in current use. Here we investigate the efficacy of topical treatment with HePC in mice infected with Leishmania mexicana or L. major, causative agents of cutaneous leishmaniasis in the New and Old World, respectively. BALB/c, CBA/J and C57BL/6 inbred mice do not control infection with L. mexicana because they do not mount an efficient Th1-type anti-parasitic lymphocyte response. In contrast, C57BL/6 mice are resistant to an infection with L. major, developing only transient lesions that heal spontaneously owing to an efficient Th1 response. BALB/c, CBA/J and C57BL/6 mice were infected subcutaneously with L. mexicana amastigotes, causing nodular lesions after 5 months. Topical treatment with HePC (Miltex) was highly effective in reducing parasite burden and healed established lesions. The treatment did not induce a Th1 response in L. mexicana-infected susceptible mice and most of the mice relapsed. In resistant C57BL/6 mice infected subcutaneously with 2 x 10(6) L. major promastigotes at the tail base, nodular lesions developed after 2 weeks. Topical treatment with Miltex reduced the parasite load and the mice healed their lesions much faster than the untreated infected controls. The clinical application of Miltex for treatment of cutaneous leishmaniasis may be highly efficient because humans, similarly to resistant mice, in general do not relapse after healing. Clinical trials should be straightforward considering that Miltex is an approved drug for the treatment of breast cancer metastases.
TL;DR: The fucose-mannose ligand-ELISA assay showed a sensitivity and a specificity of 100% in diagnosis of canine visceral leishmaniasis (CVL) (kala-azar) in sera from naturally infected dogs from São Gonçalo do Amaranto, Rio Grande de Norte, Brazil, and represents a useful tool for field control of the disease.
Abstract: The fucose-mannose ligand (FML)-ELISA assay showed a sensitivity of 100% and a specificity of 100% in diagnosis of canine visceral leishmaniasis (CVL) (kala-azar) in sera from naturally infected dogs from Sao Goncalo do Amaranto, Rio Grande de Norte, Brazil. The overall prevalence of antibodies to Leishmania in the endemic area was 23% (79 of 343). Seroreactivity detected by a Leishmania chagasi immunofluorescent (IF) assay was much lower (2.9%) and similar to the percentage of dogs with kala-azar symptoms (2.6%). Twenty-one of 21 asymptomatic, FML-seropositive animals died of kala-azar in a period ranging from 0 to 6 months after diagnosis. The predictive value was 100% for the FML-ELISA, 43% for an L. mexicana ELISA, and 24% for the L. mexicana and L. chagasi IF assays, respectively. In experimentally infected dogs, all assays detected seropositivity between 90 and 120 days after infection. Since the current strategy for control of CVL is based on detection and destruction of infected dogs, the highly predictive, sensitive, and specific FML-ELISA represents a useful tool for field control of the disease.
TL;DR: Miltefosine was originally developed as an antineoplastic drug, but it has the potential to become the first highly effective, orally administered drug for treating visceral leishmaniasis.
Abstract: Miltefosine was originally developed as an antineoplastic drug, but it has the potential to become the first highly effective, orally administered drug for treating visceral leishmaniasis, a life-t...
TL;DR: The results demonstrate that the flow cytometric membrane potential assay can be used as an easy and reliable tool for studying the evolution of interactions between amphotericin B and the parasite membrane during long-term treatments.
Abstract: Amphotericin B susceptibility was measured by a flow cytometric membrane potential assay in Leishmania infantum promastigotes isolated from 11 immunocompetent children treated with liposomal amphotericin B and 19 HIV-infected young adults treated with intralipid amphotericin B. Susceptibility levels were measured by the 90% inhibitory concentrations (IC90) representing the concentrations of drug that induced a 90% decrease in membrane potential compared with the control culture. In immunocompetent children, treatment was fully effective whatever the susceptibility of isolates to amphotericin B. In immunocompromised adults, on the contrary, unresponsiveness and relapses could be observed in all cases and IC90 increased in the course of successive treatments: a decrease of amphotericin B susceptibility in both promastigote and amastigote forms could be observed in a patient who had six relapses. These results suggest that the success of amphotericin B treatment depends greatly on patient immunity status, and indicate that successive relapses could enhance emergence of amphotericin B resistant isolates. The results demonstrate that the flow cytometric membrane potential assay can be used as an easy and reliable tool for studying the evolution of interactions between amphotericin B and the parasite membrane during long-term treatments.
TL;DR: Sera from confirmed cases of visceral leishmaniasis (VL) were seropositive using 5 ng of rORFF and serum diluted 1:20, and there was a positive correlation between spleen size and level of seropositivity with r ORFF or SA.
Abstract: The serodiagnostic potential of recombinant ORFF protein (rORFF) from Leishmania infantum was assessed by ELISA. Of 49 sera from confirmed cases of visceral leishmaniasis (VL), all were seropositive using 5 ng of rORFF and serum diluted 1:20, while only 38 were positive with 500 ng of soluble antigen (SA) and 44 were positive by a direct agglutination test. There was also a positive correlation between spleen size and level of seropositivity with rORFF or SA. The reciprocal endpoint titer with rORFF was 1,280 for sera from VL patients, but < 20 with sera from malaria, filariasis, and tuberculosis patients, as well as with sera from healthy individuals from endemic and non-endemic areas. Sera from 10 confirmed cutaneous leishmaniasis cases from Turkey were negative or only weakly positive with rORFF although 9 were positive with SA. Thus, rORFF protein appears useful as a sensitive reagent for the differential diagnosis of VL caused by the Leishmania donovani complex.