No abstract

In its severe form, kala-azar, a neglected tropical disease, initiates a systemic inflammatory response that leads to DIC and other manifestations. Children may have higher risk of death due to the more intense cytokine release. The data supports the notion that IL-6 is the central cytokine that is associated with lethal disease, but interferon-gamma, IL1beta, IL-8, and TNF-alpha are also involved with disease severity. Inhibition of IL-6 is a potential target of adjuvant therapy for severe or pediatric forms of this disease.

Introduction: The objective of the study is to identify the main risk factors for death by New World visceral leishmaniasis and establish a coherent pathogenic substrate of severe disease based on clinical findings. Methods: Seventy-six deceased inpatients and 320 successfully treated inpatients with VL were studied in a case control study. Results: Bacterial infection and bleeding were mutually exclusive events leading to death. Five risk factors were unique for death by bacterial infection (malnutrition, pulmonary rales, severe anemia, severe absolute neutropenia and higher neutrophil count), while another six were unique for death by bleeding (jaundice, severe relative neutropenia, severe thrombocytopenia, liver injury, kidney failure, higher bone marrow parasite load). Bacterial infection, bleeding, severe anemia, diarrhea, dyspnea, edema, jaundice and bone marrow parasite load were the main syndromes of visceral leishmaniasis among successfully treated patients. Conclusions: The data support the idea that bacterial infections are due to immune paralysis. Broad organ and system involvement is plausibly due to the high production of proinflammatory cytokines, whose actions fit well with visceral leishmaniasis. The syndromes and causative mediators are typical of a slowly developing systemic inflammatory response syndrome. Keywords: Visceral leishmaniasis. Kala-azar. Severe inflammatory response syndrome. AIDS. Bleeding. RESUMO Introdução: O objetivo do estudo foi identificar os principais fatores de risco para morte na leishmaniose visceral do Novo Mundo e estabelecer um substrato patogênico baseado nos achados clínicos coerente para doença grave. Métodos: Em um estudo caso-controle, foram estudados 76 pacientes internados que faleceram e 320 pacientes internados tratados com sucesso. Resultados: Infecção bacteriana e sangramento foram eventos que levaram à morte, mutuamente exclusivos. Cinco fatores de risco foram únicos para morte por infecção bacteriana (desnutrição, estertores pulmonares, anemia grave, neutropenia absoluta grave e número de leucócitos aumentados), enquanto outros seis foram exclusivos para morte por sangramento (icterícia, neutropenia relativa grave, trombocitopenia grave, lesão hepática, insuficiência renal, maior carga de parasitas na medula óssea). Entre os pacientes tratados com sucesso, as principais síndromes de leishmaniose visceral foram infecções bacterianas, sangramento, anemia grave, diarreia, dispneia, edema, icterícia e carga de parasitas na medula óssea. Conclusões: Os dados apoiam a ideia de que as infecções bacterianas são secundárias a imunoparalisia. O amplo envolvimento de órgãos e sistemas é de forma plausível devido a elevada produção de citocinas pró-inflamatórias, cujas ações se encaixam com a leishmaniose visceral. As síndromes e os mediadores causais são típicos da síndrome de resposta inflamatória sistêmica, desenrolando-se lentamente. Palavras-chaves: Leishmaniose visceral. Calazar. Síndrome da resposta inflamatória sistêmica. AIDS. Sangramento.

BackgroundMiltefosine has been used successfully to treat visceral leishmaniasis (VL) in India, but it was unsuccessful for VL in a clinical trial in Brazil.MethodsTo identify molecular markers that predict VL treatment failure whole genome sequencing of 26 L. infantum isolates, from cured and relapsed patients allowed a GWAS analysis of SNPs, gene and chromosome copy number variations.FindingsA strong association was identified (p = 0·0005) between the presence of a genetically stable L. infantumMiltefosine Sensitivity Locus (MSL), and a positive response to miltefosine treatment. The risk of treatment failure increased 9·4-fold (95% CI 2·11–53·54) when an isolate did not have the MSL. The complete absence of the MSL predicted miltefosine failure with 0·92 (95% CI 0·65–0·996) sensitivity and 0·78 (95% CI 0·52–0·92) specificity. A genotyping survey of L. infantum (n = 157) showed that the frequency of MSL varies in a cline from 95% in North East Brazil to <5% in the South East. The MSL was found in the genomes of all L. infantum and L. donovani sequenced isolates from the Old World (n = 671), where miltefosine can have a cure rate higher than 93%.InterpretationKnowledge on the presence or absence of the MSL in L. infantum will allow stratification of patients prior to treatment, helping to establish better therapeutic strategies for VL treatment.FundCNPq, FAPES, GCRF MRC and Wellcome Trust.

Background:A possible strategy to reduce fatality rates of visceral leishmaniasis is to identify prognostic factors that can be easily assessed and used as an aid to clinical decision-making. Patients and Methods: A case-control study was developed in Teresina, Brazil, in which cases were patients who died during treatment (n = 12) and controls (n = 78) comprised a random sample of patients who were alive when treatment was finished. Results: Variables significantly associated with death were severe anemia, fever for more than 60 days, diarrhea and jaundice. The prognostic system had a sensitivity of 85.7% and a specificity of 92.5%. Conclusion: The prognostic model developed in this study had satisfactory performance and might be useful in developing countries, since it is simple and inexpensive. However, it is still preliminary and needs to be improved and validated using larger and more recent samples.

Genotypes of the MBL2 gene predict the risk for developing VL and clinical complications in infections with L. chagasi.

ABSTRACTDespite the clear need to control visceral leishmaniasis (VL), the existing diagnostic tests have serious shortcomings. Here, we introduce an innovative approach to directly identifyLeishmania infantumantigens producedin vivoin humans with VL. We combined reverse-phase high-performance liquid chromatography (RP-HPLC) with mass spectrometry and categorized three distinctL. infantumproteins presumably produced in bone marrow/spleen/liver and excreted in the urine of patients with VL. The genes coding for these proteins (L. infantumiron superoxide dismutase, NCBI accession numberXP_001467866.1;L. infantumtryparedoxin, NCBI accession numberXP_001466642.1; andL. infantumnuclear transport factor 2, NCBI accession numberXP_001463738.1) were cloned, and the recombinant molecules were produced inEscherichia coli. Antibodies to these proteins were produced in rabbits and chickens and were used to develop a capture enzyme-linked immunosorbent assay (ELISA) designed to detect theseL. infantumantigens in the urine of VL patients. Specificity of the antibodies was confirmed by a Western blot analysis using both recombinant proteins and whole parasite extract. Importantly, a urinary antigen detection assay assembled with pairs of antibodies specific for each of these antigens identified 17 of 19 patients with VL. These results indicate that an improved antigen detection assay based onL. infantumproteins present in the urine of patients with VL may represent an important new strategy for the development of a specific and accurate diagnostic test that has the potential to both distinguish active VL from asymptomatic infection and serve as an important tool to monitor therapy efficacy.

BackgroundThere is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option.MethodsA multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb+5/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb+5/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption.Results378 patients were randomized to the four treatment arms: MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003).ConclusionsDue to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738.Trial registrationClinicalTrials.gov NCT01310738