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1.
PLoS Negl Trop Dis ; 14(7): e0008429, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32687498

RESUMO

BACKGROUND: Few prospective data exist on incidence of post kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis (VL) relapse after different treatment regimens. METHODOLOGY/PRINCIPAL FINDINGS: A Phase IV trial included 1761 VL patients treated between 2012-2014 with single dose AmBisome (SDA; N = 891), miltefosine-paromomycin (Milt-PM; n = 512), or AmBisome-miltefosine (AmB-Milt; n = 358). Follow-up for PKDL and VL relapse was scheduled for 6, 12 and 24 months after treatment, lasting until 2017. Patients with lesions consistent with PKDL were tested by rK39 rapid test, and if positive, underwent skin-snip sampling, smear microscopy and PCR. Probable PKDL was defined by consistent lesions and positive rK39; confirmed PKDL required additional positive microscopy or PCR. PKDL and relapse incidence density were calculated by VL treatment and risk factors evaluated in Cox proportional hazards models. Among 1,750 patients who completed treatment, 79 had relapse and 104 PKDL. Relapse incidence density was 1.58, 2.08 and 0.40 per 1000 person-months for SDA, AmB-Milt and Milt-PM, respectively. PKDL incidence density was 1.29, 1.45 and 2.65 per 1000 person-months for SDA, AmB-Milt and Milt-PM. In multivariable models, patients treated with Milt-PM had lower relapse but higher PKDL incidence than those treated with SDA; AmB-Milt rates were not significantly different from those for SDA. Children <12 years were at higher risk for both outcomes; females had a higher risk of PKDL but not relapse. CONCLUSIONS/SIGNIFICANCE: Active surveillance for PKDL and relapse, followed by timely treatment, is essential to sustain the achievements of VL elimination programs in the Indian sub-continent.


Assuntos
Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Índia/epidemiologia , Leishmaniose Cutânea/patologia , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Adulto Jovem
2.
Parasit Vectors ; 13(1): 159, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228668

RESUMO

The 5th Post-Kala-Azar Dermal Leishmaniasis (PKDL) Consortium meeting brought together PKDL experts from all endemic areas to review and discuss existing and new data on PKDL. This report summarizes the presentations and discussions and provides the overall conclusions and recommendations.


Assuntos
Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/epidemiologia , Animais , Humanos , Cinética , Vacinas contra Leishmaniose , Leishmaniose Cutânea , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/terapia , Sri Lanka/epidemiologia , Xenodiagnóstico
3.
PLoS Negl Trop Dis ; 14(1): e0007995, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31995564

RESUMO

BACKGROUND: Bangladesh, India, and Nepal aim for the elimination of Visceral Leishmaniasis (VL), a systemic parasitic infectious disease, as a public health problem by 2020. For decades, male patients have comprised the majority of reported VL cases in this region. By comparing this reported VL sex ratio to the one observed in population-based studies conducted in the Indian subcontinent, we tested the working hypothesis that mainly socio-cultural gender differences in healthcare-seeking behavior explain this gender imbalance. METHODOLOGY/PRINCIPAL FINDINGS: We compared the observed sex ratio of male versus female among all VL cases reported by the health system in Nepal and in the two most endemic states in India with that observed in population-based cohort studies in India and Nepal. Also, we assessed male sex as a potential risk factor for seroprevalence at baseline, seroconversion, and VL incidence in the same population-based data. The male/female ratio among VL cases reported by the health systems was 1.40 (95% CI 1.37-1.43). In the population cohort data, the age- and study site-adjusted male to female risk ratio was 1.27 (95% CI 1.08-1.51). Also, males had a 19% higher chance of being seropositive at baseline in the population surveys (RR 1.19; 95% CI 1.11-1.27), while we observed no significant difference in seroconversion rate between both sexes at the DAT cut-off titer defined as the primary endpoint. CONCLUSIONS/SIGNIFICANCE: Our population-based data show that male sex is a risk factor for VL, and not only as a socio-cultural determinant. Biological sex-related differences likely play an important role in the pathogenesis of this disease.


Assuntos
Notificação de Doenças/estatística & dados numéricos , Leishmaniose Visceral/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Instalações de Saúde , Humanos , Incidência , Lactente , Leishmaniose Visceral/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Razão de Masculinidade , Adulto Jovem
4.
Lancet Glob Health ; 8(2): e237-e243, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31981555

RESUMO

BACKGROUND: Nepal launched a visceral leishmaniasis (also known as kala-azar) elimination initiative in 2005. We primarily aimed to assess whether transmission of Leishmania donovani had decreased since the launch of the initiative. We also assessed the validity of the direct agglutination test (DAT) as a marker of infection, in view of future surveillance systems. METHODS: We did a repeat survey in a population aged 2 years and older for whom baseline serological data were available from 2006. Data were from three districts in the eastern region of Nepal. The primary outcome of interest was prevalent infection with L donovani as measured with DAT (cutoff value ≥1:3200). We compared age group-specific and cluster-specific seroprevalences in 2016 with those in 2006, using χ2 tests, with a specific focus on the comparison of seroprevalences in children born between 1996 and 2005, and those born between 2006 and 2015. To estimate the overall adjusted risk ratio for being seropositive in 2016 compared with 2006, we fitted a Poisson model controlling for age, sex, and cluster. FINDINGS: Between Oct 17, 2016, and Dec 26, 2016, we assessed 6609 individuals. DAT prevalence in children younger than 10 years was 4·1% (95% CI 3·2-5·4) in 2006 versus 0·5% (0·1-1·7) in 2016 (p<0·0001). Seroprevalence was lower in 2016 than in 2006 in all age groups and in all repeated clusters. The overall adjusted risk ratio of being seropositive was 0·44 (95% CI 0·37-0·52) for 2016 compared with 2006, and 0·04 (0·01-0·16) in children younger than 10 years. INTERPRETATION: Our findings show that transmission of L donovani in Nepal has decreased significantly between 2006 and 2016, coinciding with the elimination programme. DAT seems useful for monitoring of L donovani transmission. FUNDING: The Directorate-General for Development Cooperation of Belgium.


Assuntos
Erradicação de Doenças/estatística & dados numéricos , Erradicação de Doenças/tendências , Doenças Endêmicas/prevenção & controle , Leishmania donovani/imunologia , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/prevenção & controle , Leishmaniose Visceral/transmissão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Doenças Endêmicas/estatística & dados numéricos , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Nepal/epidemiologia , Fatores de Risco , Estudos Soroepidemiológicos , Inquéritos e Questionários , Adulto Jovem
5.
PLoS Negl Trop Dis ; 13(12): e0007900, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830038

RESUMO

Whole genome sequencing (WGS) is increasingly used for molecular diagnosis and epidemiology of infectious diseases. Current Leishmania genomic studies rely on DNA extracted from cultured parasites, which might introduce sampling and biological biases into the subsequent analyses. Up to now, direct analysis of Leishmania genome in clinical samples is hampered by high levels of human DNA and large variation in parasite load in clinical samples. Here, we present a method, based on target enrichment of Leishmania donovani DNA with Agilent SureSelect technology, that allows the analysis of Leishmania genomes directly in clinical samples. We validated our protocol with a set of artificially mixed samples, followed by the analysis of 63 clinical samples (bone marrow or spleen aspirates) from visceral leishmaniasis patients in Nepal. We were able to identify genotypes using a set of diagnostic SNPs in almost all of these samples (97%) and access comprehensive genome-wide information in most (83%). This allowed us to perform phylogenomic analysis, assess chromosome copy number and identify large copy number variants (CNVs). Pairwise comparisons between the parasite genomes in clinical samples and derived in vitro cultured promastigotes showed a lower aneuploidy in amastigotes as well as genomic differences, suggesting polyclonal infections in patients. Altogether our results underline the need for sequencing parasite genomes directly in the host samples.


Assuntos
Genótipo , Leishmania/classificação , Leishmania/genética , Leishmaniose Visceral/parasitologia , Manejo de Espécimes/métodos , Sequenciamento Completo do Genoma/métodos , Adolescente , Criança , Pré-Escolar , DNA de Protozoário/química , DNA de Protozoário/genética , Humanos , Lactente , Leishmania/isolamento & purificação , Nepal
6.
Infect Genet Evol ; 76: 104073, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31629887

RESUMO

Visceral leishmaniasis (VL), the most severe form of the disease, is caused by Leishmania donovani in the Indian sub-continent (ISC). Whole genome sequencing studies revealed that two parasite populations exist in the ISC: a main population named the Core Group (CG) found mostly in the lowlands, and a new, genetically different subpopulation called ISC1. Parasites belonging to the CG were shown to be responsible for the recent epidemics, while the ISC1 variant was originally identified in hilly districts of Nepal and was later on increasingly found in the lowlands. Importantly, the ISC1 and CG isolates differ in their drug susceptibility and virulence signatures, suggesting that ISC1 constitutes an emerging and functionally different variant of L. donovani. In present study we aimed to address the potential of ISC1 transmission by the natural vector of L. donovani in the lowlands, Phlebotomus argentipes. By experimental infection of sand flies with parasites of the different genotypes, we demonstrate that ISC1 and CG strains are developing similarly in P. argentipes, suggesting that P. argentipes is a fully competent vector for ISC1 parasites. Integration of previous and current findings shows thus that ISC1 is a new and different variant of L. donovani, fully adapted to spread in the ISC through the main vector. This information is directly useful for managers of the elimination program. Furthermore, integration of our successive studies (genotyping, phenotyping and vector competence) demonstrates the relevance of molecular surveillance and should be of interest for scientists working on vector borne diseases and control managers.


Assuntos
Leishmania donovani/classificação , Leishmaniose Visceral/transmissão , Phlebotomus/parasitologia , Animais , Feminino , Humanos , Índia , Insetos Vetores/parasitologia , Leishmania donovani/genética , Leishmania donovani/isolamento & purificação , Filogenia
7.
PLoS Negl Trop Dis ; 13(9): e0007726, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31557162

RESUMO

BACKGROUND: An earlier open label, prospective, non-randomized, non-comparative, multi-centric study conducted within public health facilities in Bihar, India (CTRI/2012/08/002891) measured the field effectiveness of three new treatment regimens for visceral leishmaniasis (VL): single dose AmBisome (SDA), and combination therapies of AmBisome and miltefosine (AmB+Milt) and miltefosine and paromomycin (Milt+PM) up to 6 months follow-up. The National Vector Borne Disease Control Program (NVBDCP) recommended an extended follow up at 12 months post-treatment of the original study cohort to quantify late relapses. METHODS: The 1,761 patients enrolled in the original study with the three new regimens were contacted and traced between 10 and 36 months following completion of treatment to determine their health status and any occurrence of VL relapse. RESULTS: Of 1,761 patients enrolled in the original study, 1,368 were traced at the extended follow-up visit: 711 (80.5%), 295 (83.2%) and 362 (71.5%) patients treated with SDA, AmB+Milt and Milt+PM respectively. Of those traced, a total of 75 patients were reported to have relapsed by the extended follow-up; 45 (6.3%) in the SDA, 25 (8.5%) in the AmB+Milt and 5 (1.4%) in the Milt+PM arms. Of the 75 relapse cases, 55 had already been identified in the 6-months follow-up and 20 were identified as new cases of relapse at extended follow-up; 7 in the SDA, 10 in the AmB+Milt and 3 in the Milt+PM arms. CONCLUSION: Extending follow-up beyond the standard 6 months identified additional relapses, suggesting that 12-month sentinel follow-up may be useful as a programmatic tool to better identify and quantify relapses. With limited drug options, there remains an urgent need to develop effective new chemical entities (NCEs) for VL.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Adolescente , Anfotericina B/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Índia , Masculino , Paromomicina/uso terapêutico , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Recidiva , Resultado do Tratamento
9.
Can J Infect Dis Med Microbiol ; 2019: 9392414, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467623

RESUMO

Post-kala-azar dermal leishmaniasis (PKDL) is a skin manifestation of visceral leishmaniasis (VL) which develops after apparent cure in some patients. PKDL is considered as the potential reservoir for the VL infection. Molecular epidemiological characterization of L. donovani isolates obtained from VL and PKDL isolates is essentially required in order to understand the transmission dynamics of the VL infection. To date, genetic variation among the VL and PKDL L. donovani isolates was not fully elucidated. Therefore, 14 clinical isolates from VL and 4 clinical isolates from PKDL were speciated by hsp70 and rDNA genes. Further characterization of L. donovani by haspB PCR demonstrates two different genotypes. All PKDL isolates have the same genetic structure. kDNA PCR-RFLP assay revealed 18 different genotypes; however, structural analysis showed the two distinct kDNA genotype population (k = 2). The kDNA fingerprint patterns of parasites from hilly districts were clustered separately from low-land districts. Therefore, further study with a large number of samples is urgently required for systematic characterization of the clinical isolates to track the molecular epidemiology of the Leishmania donovani causing VL and the role of PKDL as a reservoir.

10.
JNMA J Nepal Med Assoc ; 57(215): 25-28, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080241

RESUMO

INTRODUCTION: The diagnosis of the spinal lesions often puts the clinician in dilemma. The definite diagnosis is obviously needed for the proper management of the disease. The wrong diagnosis not only imposes the adverse effects, but sometimes may lead to the disabling conditions and even prove to be life threatening. This study is aimed at evaluating the need of fluoroscopy guided percutaneous transpedicular biopsy for establishing the proper diagnosis and find the diagnostic yield. METHODS: This is the descriptive cross-sectional study conducted over the period of 10 years in the Upendra Devkota Memorial National Institute of Neurological and Allied Sciences among the patients who underwent transpedicular biopsy for various spinal lesions. RESULTS: Among the 77 cases, 38 (49%) of the lesions on MRI were single level whereas 39 (51%) of the lesions were multiple. Most of the lesions were diagnosed as the non-tubercular infection 30 (42%), followed by the osteoporotic fractures and malignancy in 18 (25%) and 15 (21%) respectively. The sensitivity and specificity of the radiology with the background of clinical scenario was 79.5% and 90.9% respectively. The diagnostic yield of the biopsy was 93.5%. CONCLUSIONS: The transpedicular biopsy of the spinal lesion is the must for the proper diagnosis and treatment plan of such cases. The change in the diagnosis after biopsy is often possible which will drastically alter the treatment plan.


Assuntos
Biópsia/métodos , Fluoroscopia/métodos , Doenças da Coluna Vertebral/diagnóstico , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nepal , Sensibilidade e Especificidade , Doenças da Coluna Vertebral/patologia
14.
PLoS Negl Trop Dis ; 12(10): e0006830, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30346949

RESUMO

BACKGROUND: In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions. METHODS: This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891. RESULTS: Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related. CONCLUSION: All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India. TRIAL REGISTRATION: Clinical trial is registered at Clinical trial registry of India (CTRI/2012/08/002891, Registered on 16/08/2012, Trial Registered Prospectively).


Assuntos
Antiprotozoários/administração & dosagem , Antiprotozoários/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Leishmaniose Visceral/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anfotericina B/administração & dosagem , Anfotericina B/efeitos adversos , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Paromomicina/administração & dosagem , Paromomicina/efeitos adversos , Fosforilcolina/administração & dosagem , Fosforilcolina/efeitos adversos , Fosforilcolina/análogos & derivados , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
15.
Clin Microbiol Rev ; 31(4)2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30158301

RESUMO

Research in visceral leishmaniasis in the last decade has been focused on how better to use the existing medicines as monotherapy or in combination. Systematic research by geographical regions has shown that a universal treatment is far from today's reality. Substantial progress has been made in the elimination of kala-azar in South Asia, with a clear strategy on first- and second-line therapy options of single-dose liposomal amphotericin B and a combination of paromomycin and miltefosine, respectively, among other interventions. In Eastern Africa, sodium stibogluconate (SSG) and paromomycin in combination offer an advantage compared to the previous SSG monotherapy, although not exempted of limitations, as this therapy requires 17 days of painful double injections and bears the risk of SSG-related cardiotoxicity. In this region, attempts to improve the combination therapy have been unsuccessful. However, pharmacokinetic studies have led to a better understanding of underlying mechanisms, like the underexposure of children to miltefosine treatment, and an improved regimen using an allometric dosage. Given this global scenario of progress and pitfalls, we here review what steps need to be taken with existing medicines and highlight the urgent need for oral drugs. Furthermore, it should be noted that six candidates belonging to five new chemical classes are reaching phase I, ensuring an optimistic near future.


Assuntos
Antiprotozoários/uso terapêutico , Descoberta de Drogas/tendências , Leishmaniose Visceral/tratamento farmacológico , Pesquisa Biomédica/tendências , Humanos
16.
Sci Rep ; 8(1): 11765, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082744

RESUMO

The growing drug resistance (DR) raises major concerns for the control of visceral leishmaniasis (VL), a neglected disease lethal in 95 percent of the cases if left untreated. Resistance has rendered antimonials (SSG) obsolete in the Indian Sub-Continent (ISC) and the first miltefosine-resistant Leishmania donovani were isolated. New chemotherapeutic options are needed and novel compounds are being identified by high-throughput screening (HTS). HTS is generally performed with old laboratory strains such as LdBOB and we aimed here to validate the activity of selected compounds against recent clinical isolates. In this academic/industrial collaboration, 130 compounds from the GSK "Leishbox" were screened against one SSG-sensitive and one SSG-resistant strain of L. donovani recently isolated from ISC patients, using an intracellular assay of L. donovani-infected THP1-derived macrophages. We showed that only 45% of the compounds were active in both clinical isolates and LdBOB. There were also different compound efficiencies linked to the SSG susceptibility background of the strains. In addition, our results suggested that the differential susceptibility profiles were chemical series-dependent. In conclusion, we demonstrate the potential value of including clinical isolates (as well as resistant strains) in the HTS progression cascade.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania donovani/patogenicidade , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Descoberta de Drogas , Resistência a Medicamentos , Humanos , Leishmania donovani/efeitos dos fármacos , Macrófagos/parasitologia , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Células THP-1
17.
Infect Genet Evol ; 62: 170-178, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29679745

RESUMO

Leishmania donovani is the responsible agent for visceral leishmaniasis (VL) in the Indian subcontinent (ISC). The disease is lethal without treatment and causes 0.2 to 0.4 million cases each year. Recently, reports of VL in Nepalese hilly districts have increased as well as VL cases caused by L. donovani from the ISC1 genetic group, a new and emerging genotype. In this study, we perform for the first time an integrated, untargeted genomics and metabolomics approach to characterize ISC1, in comparison with the Core Group (CG), main population that drove the most recent outbreak of VL in the ISC. We show that the ISC1 population is very different from the CG, both at genome and metabolome levels. The genomic differences include SNPs, CNV and small indels in genes coding for known virulence factors, immunogens and surface proteins. Both genomic and metabolic approaches highlighted dissimilarities related to membrane lipids, the nucleotide salvage pathway and the urea cycle in ISC1 versus CG. Many of these pathways and molecules are important for the interaction with the host/extracellular environment. Altogether, our data predict major functional differences in ISC1 versus CG parasites, including virulence. Therefore, particular attention is required to monitor the fate of this emerging ISC1 population in the ISC, especially in a post-VL elimination context.


Assuntos
Leishmania donovani/genética , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/parasitologia , Genoma de Protozoário , Genômica , Humanos , Índia/epidemiologia , Metabolômica , Polimorfismo de Nucleotídeo Único
18.
Artigo em Inglês | MEDLINE | ID: mdl-30619774

RESUMO

Background: There is a recognized need for an improved diagnostic test to assess post-chemotherapeutic treatment outcome in visceral leishmaniasis (VL) and to diagnose post kala-azar dermal leishmaniasis (PKDL). We previously demonstrated by ELISA and a prototype novel rapid diagnostic test (RDT), that high anti-Leishmania IgG1 is associated with post-treatment relapse versus cure in VL. Methodology: Here, we further evaluate this novel, low-cost RDT, named VL Sero K-SeT, and ELISA for monitoring IgG1 levels in VL patients after treatment. IgG1 levels against L. donovani lysate were determined. We applied these assays to Indian sera from cured VL at 6 months post treatment as well as to relapse and PKDL patients. Sudanese sera from pre- and post-treatment and relapse were also tested. Results: Of 104 paired Indian sera taken before and after treatment for VL, when deemed clinically cured, 81 (77.9%) were positive by VL Sero K-SeT before treatment; by 6 months, 68 of these 81 (84.0%) had a negative or reduced RDT test line intensity. ELISAs differed in positivity rate between pre- and post-treatment (p = 0.0162). Twenty eight of 33 (84.8%) Indian samples taken at diagnosis of relapse were RDT positive. A comparison of Indian VL Sero K-SeT data from patients deemed cured and relapsed confirmed that there was a significant difference (p < 0.0001) in positivity rate for the two groups using this RDT. Ten of 17 (58.8%) Sudanese sera went from positive to negative or decreased VL Sero K-SeT at the end of 11-30 days of treatment. Forty nine of 63 (77.8%) PKDL samples from India were positive by VL Sero K-SeT. Conclusion: We have further shown the relevance of IgG1 in determining clinical status in VL patients. A positive VL Sero K-SeT may also be helpful in supporting diagnosis of PKDL. With further refinement, such as the use of specific antigens, the VL Sero K-SeT and/or IgG1 ELISA may be adjuncts to current VL control programmes.


Assuntos
Imunoglobulina G/sangue , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/imunologia , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/terapia , Antígenos de Protozoários/imunologia , Testes Diagnósticos de Rotina , Ensaio de Imunoadsorção Enzimática , Humanos , Testes Imunológicos , Índia , Leishmania donovani/imunologia , Leishmania donovani/patogenicidade , Kit de Reagentes para Diagnóstico , Recidiva , Sudão
19.
Indian J Med Res ; 148(4): 385-395, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30666001

RESUMO

Background & objectives: Although febrile illnesses are a frequent cause of consultation and hospitalization in low- and middle-income countries (LMICs), research has mainly focused on acute febrile illnesses (AFIs). In contrast, there are limited data on the causes of persistent febrile illnesses (PFIs) in LMIC. Lack of clarity on the differential diagnosis of PFIs in the rural tropics leads to the absence of diagnostic guidance tools. Methods: In this study, a review of the potential causes of persistent fever defined as fever of more than seven days was done in Nepal, with a focus on nine pathogen-specific conditions. The current knowledge on their burden, distribution and diagnosis was summarized. Results: Limited data were found on the incidence and public health burden of leptospirosis, murine typhus and brucellosis due to the absence of diagnostic tools outside reference laboratories and the overlap of signs and symptoms with other febrile conditions. The incidence of malaria and visceral leishmaniasis (VL) was found to be decreasing in Nepal, with some changes of the geographical areas at risk. Interpretation & conclusions: This review indicates a need for more research on the causes of PFIs in Nepal and in the region and for the development of clinical guidance tailored to current local epidemiology. Guidance tools should include specific clinical features (e.g. eschar), results of rapid diagnostic tests (e.g. malaria, VL), appropriate indications for more sophisticated tests (e.g. abdominal ultrasound, polymerase chain reaction) and recommendations for adequate use of empirical treatment.


Assuntos
Febre/etiologia , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Negativas/epidemiologia , Leishmaniose Visceral/epidemiologia , Malária/epidemiologia , Tuberculose/epidemiologia , Brucelose/complicações , Brucelose/epidemiologia , Humanos , Incidência , Leishmaniose Visceral/complicações , Leptospirose/complicações , Leptospirose/epidemiologia , Abscesso Hepático Amebiano/complicações , Abscesso Hepático Amebiano/epidemiologia , Malária/complicações , Melioidose/complicações , Melioidose/epidemiologia , Nepal/epidemiologia , Tuberculose/complicações , Febre Tifoide/complicações , Febre Tifoide/epidemiologia , Tifo Endêmico Transmitido por Pulgas/complicações , Tifo Endêmico Transmitido por Pulgas/epidemiologia
20.
BMC Infect Dis ; 17(1): 791, 2017 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-29273010

RESUMO

BACKGROUND: Leishmania donovani is the etiological agent of visceral leishmaniasis (VL) in the Indian subcontinent. However, it is also known to cause cutaneous leishmaniasis (CL) in Sri Lanka. Sri Lankan L. donovani differs from other L. donovani strains, both at the molecular and biochemical level. To investigate the different species or strain-specific differences of L. donovani in Sri Lanka we evaluated sequence variation of the kinetoplastid DNA (kDNA). METHODS: Parasites isolated from skin lesions of 34 CL patients and bone marrow aspirates from 4 VL patients were genotyped using the kDNA minicircle PCR analysis. A total of 301 minicircle sequences that included sequences from Sri Lanka, India, Nepal and six reference species of Leishmania were analyzed. RESULTS: Haplotype diversity of Sri Lankan isolates were high (H d = 0.757) with strong inter-geographical genetic differentiation (F ST > 0.25). In this study, L. donovani isolates clustered according to their geographic origin, while Sri Lankan isolates formed a separate cluster and were clearly distinct from other Leishmania species. Within the Sri Lankan group, there were three distinct sub-clusters formed, from CL patients who responded to standard antimony therapy, CL patients who responded poorly to antimony therapy and from VL patients. There was no specific clustering of sequences based on geographical origin within Sri Lanka. CONCLUSION: This study reveals high levels of haplotype diversity of L. donovani in Sri Lanka with a distinct genetic association with clinically relevant phenotypic characteristics. The use of genetic tools to identify clinically relevant features of Leishmania parasites has important therapeutic implications for leishmaniasis.


Assuntos
Variação Genética , Leishmania donovani/genética , Leishmaniose Cutânea/diagnóstico , Medula Óssea/parasitologia , Medula Óssea/patologia , Análise por Conglomerados , Estudos Transversais , DNA de Cinetoplasto/química , DNA de Cinetoplasto/genética , DNA de Cinetoplasto/metabolismo , Genótipo , Haplótipos , Humanos , Leishmania donovani/classificação , Leishmania donovani/isolamento & purificação , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/parasitologia , Masculino , Filogenia , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Pele/parasitologia , Pele/patologia , Sri Lanka/epidemiologia
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