Human Visceral Leishmaniasis: lethality and time from suspicion to treatment in an endemic area in Brazil / Leishmaniose visceral humana: letalidade e tempo da suspeição ao tratamento em área endêmica no Brasil / Leishmaniasis visceral humana: letalidad y tiempo desde la sospecha hasta el tratamiento en un área endémica de Brasil

Background and objectives: human visceral leishmaniasis (HVL) are a persistent public health problem, configuring a challenge to reduce its lethality. In order to evaluate the factors associated with lethality, this study emphasizes the time elapsed from suspicion to treatment of HVL, in the years 2015 to 2019, in the municipality of Araguaína-TO, an area of intense transmission. Methods: an epidemiological study of case series with longitudinal follow-up with information extracted from HVL notification and investigation forms. The relative risk (RR) was used as a measure of the strength of association for death, being calculated with confidence intervals (95% CI) estimated by the Wald test. Time intervals were represented in days by box plot as medians (Md). Results: of the 191 cases of HVL, 179 (93.72%) were cured and 12 (6.28%) had a fatal outcome. There was no association of risk of death by sex, education, race, being significant only by age in the age groups of young (RR= 16.09) and older adults (RR=7.08). The time from suspicion to treatment in children was shorter (0-35 days, Md=12) than that of older patients (4-44 days, Md=18) and in those who died (7-65 days, Md=20) highlighting greater inopportunity of healing in these last two groups. Conclusion: late diagnosis was a determining indicator for worse outcomes, five days made the difference between the group with an outcome for cure with the group of those who died, highlighting the need to shorten the wait for treatment.(AU)

Justificativa e objetivos: a leishmaniose visceral humana (LVH) constitui-se em persistente problema de saúde pública, configurando-se um desafio à redução de sua letalidade. Para avaliação dos fatores associados à letalidade, este estudo tem ênfase no tempo decorrido da suspeição ao tratamento de LVH, nos anos de 2015 a 2019, no município de Araguaína-TO, área de transmissão intensa. Métodos: estudo epidemiológico de série de casos com acompanhamento longitudinal, com informações extraídas das fichas de notificação e investigação de LVH. Utilizou-se o risco relativo (RR) como medida de força de associação para o óbito, sendo calculado com intervalos de confiança (IC 95%) estimados pelo Teste de Wald. Os intervalos de tempo foram representados em dias por box plot em medianas (Md). Resultados: dos 191 casos de LVH, 179 (93,72%) obtiveram cura e 12 (6,28%) apresentaram desfecho fatal. Não houve associação de risco de morte por sexo, escolaridade, raça ou cor, sendo significativa apenas por idade nas faixas etárias de adultos jovens (RR= 16,09) e idosos (RR=7,08). O tempo da suspeição ao tratamento em crianças foi mais curto (0-35 dias, Md= 12) que o de pacientes mais velhos (4-44 dias, Md=18) e naqueles que evoluíram ao óbito (7-65 dias, Md=20), realçando maior inoportunidade de cura nesses dois últimos grupos. Conclusão: o diagnóstico tardio foi um indicador determinante para piores desfechos, e cinco dias fizeram a diferença entre o grupo com desfecho para cura e o grupo dos que vieram a óbito, destacando a necessidade de encurtamento da espera para tratamento.(AU)

Justificación y objetivos: la leishmaniasis visceral humana (HVI) constituye un problema persistente de salud pública, configurando un desafío para reducir su letalidad. Con el objetivo de evaluar los factores asociados a la letalidad, este estudio enfatiza el tiempo transcurrido desde la sospecha hasta el tratamiento de la VLH, en los años 2015 a 2019, en el municipio de Araguaína-TO, zona de transmisión intensa. Métodos: estudio epidemiológico de serie de casos con seguimiento longitudinal con información extraída de los formularios de notificación e investigación LVH. Se utilizó el riesgo relativo (RR) como medida de la fuerza de asociación para muerte, siendo calculado con intervalos de confianza (IC 95%) estimados por la prueba de Wald. Los intervalos de tiempo se representaron en días mediante diagrama de caja como medianas (Md). Resultados: los 191 casos de LVH, 179 (93,72%) se curaron y 12 (6,28%) tuvieron un desenlace fatal. No hubo asociación de riesgo de muerte por sexo, educación, raza o color, siendo significativo solo por edad en los grupos de edad de adultos jóvenes (RR= 16,09) y ancianos (RR=7,08). El tiempo desde la sospecha hasta el tratamiento en los niños fue menor (0-35 días, Md=12) que en los pacientes mayores (4-44 días, Md=18) y en los que fallecieron (7-65 días, Md=20) destacando mayor inoportunidad de curación en estos dos últimos grupos. Conclusión: el diagnóstico tardío fue un indicador determinante de peor desenlace, los cinco días marcaron la diferencia entre el grupo con resultado de curación con el grupo de los que fallecieron, destacando la necesidad de reducir la espera para el tratamiento.(AU)

American visceral leishmaniasis in a state of northeastern Brazil: clinical, epidemiological and laboratory aspects / Leishmaniose visceral americana em estado do nordeste brasileiro: aspectos clínicos, epidemiológicos e laboratoriais

In Brazil, American visceral leishmaniasis (AVL) has become a public health concern due to its high incidence and lethality. This study aimed to analyze the clinical, epidemiological, and laboratory aspects of AVL in a state of Brazil. This descriptive, cross-sectional, retrospective, and quantitative study of notified cases of AVL was carried out in Alagoas between 2008 and 2017 from data obtained from DATASUS/SINAN. Sociodemographic, clinical, and laboratory variables were analyzed. A descriptive analysis was performed using absolute values and valid percentages, using tables and/or graphs. Data processing was performed using Stata 12.0®. Results with P <0.05 were considered statistically significant. During the study period, 352 cases of AVL were reported, of which 6.82% died and 38.92% had met a cure criterion. Male patients were predominant (66.76%). Of the total infected patients, 16.76% had attended only the 1st to the 4th grades, with those most affected aged 1 to 4 years (28.69%). Laboratory diagnostic criteria were most commonly used to confirm the notified cases (76.42%), whereas 51.70% and 8.52% of the cases had positive parasitological and immunofluorescence diagnoses, respectively. Finally, the study showed a higher prevalence of the disease in children, men and in rural residents. Although with low lethality, the expressive frequency of AVL in the State of Alagoas was still verified, since there was an increase in the number of cases during the years of the study.

No Brasil, a leishmaniose visceral americana (LVA) tornou-se uma preocupação de saúde pública devido à sua alta incidência e letalidade. Este estudo teve como objetivo analisar os aspectos clínicos, epidemiológicos e laboratoriais da AVL em um estado brasileiro. Este estudo descritivo, transversal, retrospectivo e quantitativo dos casos notificados de AVL foi realizado em Alagoas entre 2008 e 2017 a partir de dados obtidos do DATASUS/SINAN. Foram analisadas variáveis sociodemográficas, clínicas e laboratoriais. Foi realizada uma análise descritiva utilizando-se valores absolutos e percentuais válidos, utilizando tabelas e/ou gráficos. O processamento dos dados foi realizado por meio do Stata 12.0®. Os resultados com P<0,05 foram considerados estatisticamente significativos. Durante o período de estudo, foram notificados 352 casos de LVA, dos quais 6,82% morreram e 38,92% atenderam a um critério de cura. Os pacientes do sexo masculino foram predominantes (66,76%). Do total de pacientes infectados, 16,76% tinham sido atendidos apenas do 1º ao 4º ano, com os mais afetados entre 1 e 4 anos (28,69%). Os critérios de diagnóstico laboratorial foram mais utilizados para confirmar os casos notificados (76,42%), enquanto 51,70% e 8,52% dos casos apresentaram diagnósticos positivos parasitológicos e imunofluorescência, respectivamente. Por fim, o estudo demonstrou maior prevalência da doença em crianças, homens e nos residentes em zona rural. Embora com letalidade baixa, constatou-se ainda a expressiva frequência da LVA no Estado de Alagoas, uma vez que houve aumento do número de casos durante os anos do estudo.

Epidemiological features and spatial-temporal distribution of visceral leishmaniasis in mainland China: a population-based surveillance study from 2004 to 2019.

BACKGROUND: Although visceral leishmaniasis (VL) was largely brought under control in most regions of China during the previous century, VL cases have rebounded in western and central China in recent decades. The aim of this study was to investigate the epidemiological features and spatial-temporal distribution of VL in mainland China from 2004 to 2019. METHODS: Incidence and mortality data for VL during the period 2004-2019 were collected from the Public Health Sciences Data Center of China and annual national epidemic reports of VL, whose data source was the National Diseases Reporting Information System. Joinpoint regression analysis was performed to explore the trends of VL. Spatial autocorrelation and spatial-temporal clustering analysis were conducted to identify the distribution and risk areas of VL transmission. RESULTS: A total of 4877 VL cases were reported in mainland China during 2004-2019, with mean annual incidence of 0.0228/100,000. VL incidence showed a decreasing trend in general during our study period (annual percentage change [APC] = -4.2564, 95% confidence interval [CI]: -8.0856 to -0.2677). Among mainly endemic provinces, VL was initially heavily epidemic in Gansu, Sichuan, and especially Xinjiang, but subsequently decreased considerably. In contrast, Shaanxi and Shanxi witnessed significantly increasing trends, especially in 2017-2019. The first-level spatial-temporal aggregation area covered two endemic provinces in northwestern China, including Gansu and Xinjiang, with the gathering time from 2004 to 2011 (relative risk [RR] = 13.91, log-likelihood ratio [LLR] = 3308.87, P < 0.001). The secondary aggregation area was detected in Shanxi province of central China, with the gathering time of 2019 (RR = 1.61, LLR = 4.88, P = 0.041). The epidemic peak of October to November disappeared in 2018-2019, leaving only one peak in March to May. CONCLUSIONS: Our findings suggest that VL is still an important endemic infectious disease in China. Epidemic trends in different provinces changed significantly and spatial-temporal aggregation areas shifted from northwestern to central China during our study period. Mitigation strategies, including large-scale screening, insecticide spraying, and health education encouraging behavioral change, in combination with other integrated approaches, are needed to decrease transmission risk in areas at risk, especially in Shanxi, Shaanxi, and Gansu provinces.

Visceral Leishmaniasis in pregnancy and vertical transmission: A systematic literature review on the therapeutic orphans.

BACKGROUND: Reports on the occurrence and outcome of Visceral Leishmaniasis (VL) in pregnant women is rare in published literature. The occurrence of VL in pregnancy is not systematically captured and cases are rarely followed-up to detect consequences of infection and treatment on the pregnant women and foetus. METHODS: A review of all published literature was undertaken to identify cases of VL infections among pregnant women by searching the following database: Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials; World Health Organization Global Index Medicus: LILACS (Americas); IMSEAR (South-East Asia); IMEMR (Eastern Mediterranean); WPRIM (Western Pacific); ClinicalTrials.gov; and the WHO International Clinical Trials Registry Platform. Selection criteria included any clinical reports describing the disease in pregnancy or vertical transmission of the disease in humans. Articles meeting pre-specified inclusion criteria and non-primary research articles such as textbook, chapters, letters, retrospective case description, or reports of accidental inclusion in trials were also considered. RESULTS: The systematic literature search identified 272 unique articles of which 54 records were included in this review; a further 18 records were identified from additional search of the references of the included studies or from personal communication leading to a total of 72 records (71 case reports/case series; 1 retrospective cohort study; 1926-2020) describing 451 cases of VL in pregnant women. The disease was detected during pregnancy in 398 (88.2%), retrospectively confirmed after giving birth in 52 (11.5%), and the time of identification was not clear in 1 (0.2%). Of the 398 pregnant women whose infection was identified during pregnancy, 346 (86.9%) received a treatment, 3 (0.8%) were untreated, and the treatment status was not clear in the remaining 49 (12.3%). Of 346 pregnant women, Liposomal amphotericin B (L-AmB) was administered in 202 (58.4%) and pentavalent antimony (PA) in 93 (26.9%). Outcomes were reported in 176 pregnant women treated with L-AmB with 4 (2.3%) reports of maternal deaths, 5 (2.8%) miscarriages, and 2 (1.1%) foetal death/stillbirth. For PA, outcomes were reported in 88 of whom 4 (4.5%) died, 24 (27.3%) had spontaneous abortion, 2 (2.3%) had miscarriages. A total of 26 cases of confirmed, probable or suspected cases of vertical transmission were identified with a median detection time of 6 months (range: 0-18 months). CONCLUSIONS: Outcomes of VL treatment during pregnancy is rarely reported and under-researched. The reported articles were mainly case reports and case series and the reported information was often incomplete. From the studies identified, it is difficult to derive a generalisable information on outcomes for pregnant women and babies, although reported data favours the usage of liposomal amphotericin B for the treatment of VL in pregnant women.

Inequalities of visceral leishmaniasis case-fatality in Brazil: A multilevel modeling considering space, time, individual and contextual factors.

BACKGROUND: In Brazil, case-fatality from visceral leishmaniasis (VL) is high and characterized by wide differences between the various political-economic units, the federated units (FUs). This study was designed to investigate the association between factors at the both FU and individual levels with the risk of dying from VL, after analysing the temporal trend and the spatial dependency for VL case-fatality. METHODOLOGY: The analysis was based on individual and aggregated data of the Reportable Disease Information System-SINAN (Brazilian Ministry of Health). The temporal and spatial distributions of the VL case-fatality between 2007 and 2017 (27 FUs as unit of analysis) were considered together with the individual characteristics and many other variables at the FU level (socioeconomic, demographic, access to health and epidemiological indicators) in a mixed effects models or multilevel modeling, assuming a binomial outcome distribution (death from VL). FINDINGS: A linear increasing temporal tendency (4%/year) for VL case-fatality was observed between 2007 and 2017. There was no similarity between the case-fatality rates of neighboring FUs (non-significant spatial term), although these rates were heterogeneous in this spatial scale of analysis. In addition to the known individual risk factors age, female gender, disease's severity, bacterial co-infection and disease duration, low level schooling and unavailability of emergency beds and health professionals (the last two only in univariate analysis) were identified as possibly related to VL death risk. Lower VL incidence was also associated to VL case-fatality, suggesting that unfamiliarity with the disease may delay appropriate medical management: VL patients with fatal outcome were notified and had VL treatment started 6 and 3 days later, respectively, in relation to VL cured patients. Access to garbage collection, marker of social and economic development, seems to be protective against the risk of dying from VL. Part of the observed VL case-fatality variability in Brazil could not be explained by the studied variables, suggesting that factors linked to the intra FU environment may be involved. CONCLUSIONS: This study aimed to identify epidemiological conditions and others related to access to the health system possibly linked to VL case-fatality, pointing out new prognostic determinants subject to intervention.

Serious adverse events following treatment of visceral leishmaniasis: A systematic review and meta-analysis.

BACKGROUND: Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs). METHODS: For this updated systematic review, we searched the following databases from 1st Jan 2016 through 2nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from individual treatment arms were combined in a meta-analysis using random effects Poisson regression. RESULTS: We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041-0.114; I2 = 81.4%; 95% prediction interval (PI): 0.001-2.779] per 1,000 person-days at risk; the rate was 0.628 [95% CI: 0.368-1.021; I2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021-0.081; I2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244-1.355; I2 = 91.9%] compared to 0.043 [95% CI: 0.020-0.090; I2 = 62.5%] in 160 arms which excluded HIV co-infections. CONCLUSION: Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our review support the need to assemble individual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research.

Epidemiological aspects of visceral leishmaniasis in the municipality of Montes Claros-MG

Visceralleishmaniasis (VL), also known as 'calazar', is a serious chronic disease caused by Leishmania species from Leishmania(Leishmania) donovanicomplex, which the disease is characterized by abdominal swelling (hepatosplenomegaly) and may evolve to death in extreme cases.In this sense, the aim of our study was to assess the epidemiological profile of the cases found in Montes Claros (Minas Gerais state).A retrospective or cross-sectional study was carried out using secondary data provided by Health Information System (SINAN/HM) of Brazil from January 2010 to February 2020. Our data has shown that VL is an endemic disease in Montes Claros region, with 413 VL cases reported, 62.00% (252) male, average age ± standard deviation (years), and 93.46% (386) lived inMontes Claros city. The presence of comorbidities was observed in 13.70% (54) of the patients and in 7.26% (30). As for the evolution of the disease, 246 (59.56%) were cured, 30 (7.26%) died due to VL. Between 2010 and 2015, Glucantime®stands out, in which 46 (11.13%) patients used the drug, followed by common Amphotericin B 24 (13.48%) and liposomal Amphotericin B 38 (21.34%). In the period between 2016 and 2020, the most prevalent drug was liposomal Amphotericin B, with 71 (29.83%) patients using it, followed by Glucantime®45 (18.9%). The condition evolved to death. We conclude thatMontes Claros is still an endemic area for VL with an increased number of cases over time and a noticeable shift in patient profile towards children and young people. Joint efforts from different areas of scientific knowledge and public health services are needed to improve the effectiveness of visceral leishmaniasis surveillance and control actions. The population can contribute to this process of disease prevention and control, through educational actions in health and the environment.

Cenário epidemiológico da Leishmaniose Visceral na Bahia / Epidemiological scenario of Visceral Leishmaniasis in Bahia

O boletim apresenta um panorama dos casos de leishmaniose visceral no estado da Bahia no período de 2008 a 2020. A maior concentração de casos no período analisado ocorreu na macrorregião de Saúde Centro-Norte, seguido da macrorregião de Saúde Centro-Leste e da macrorregião de saúde Sudoeste. Quanto a análise por Regional de Saúde, observa-se predominância de casos na regional de Saúde de Irecê, seguida da Regional de Saúde de Feira de Santana

Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis.

BACKGROUND: Visceral leishmaniasis (VL) is a vector-borne disease that is deadly if left untreated. Understanding which factors have prognostic value may help to focus clinical management and reduce case fatality. However, information about prognostic factors is scattered and conflicting. We conducted a systematic review and meta-analysis to identify prognostic factors for mortality among VL patients in East Africa. METHODOLOGY/PRINCIPAL FINDINGS: The review protocol was registered in PROSPERO (CRD42016043112). We included studies published in English after 1970 describing VL patients treated in East African health facilities. To be included, studies had to report on associations between clinical or laboratory factors and mortality during admission or during VL treatment, with a minimal study size of ten patients. Conference abstracts and evaluations of genetic or immunological prognostic factors were excluded. We searched for studies in MEDLINE and four other databases in December 2018. To assess the risk of bias in observational studies and clinical trials, we used the Quality in Prognostic Studies (QUIPS) tool. We included 48 studies in the systematic review, describing 150,072 VL patients of whom 7,847 (5.2%) died. Twelve prognostic factors were evaluated in five or more studies and these results were submitted to meta-analysis producing one pooled crude odds ratio (OR) per prognostic factor. The following factors were strongly (OR>3) and significantly (P-value<0.05) associated with mortality: jaundice (OR = 8.27), HIV (OR = 4.60), tuberculosis (OR = 4.06), age >45 years (OR = 3.69), oedema (OR = 3.52), bleeding (OR = 3.37), and haemoglobin ≤6.5 g/dl (OR = 3.26). Factors significantly and moderately (OR between one and three) associated with death were severe malnutrition, long duration of illness, young age (<5 years), and large spleen size. CONCLUSIONS/SIGNIFICANCE: These prognostic factors can be identified by health professionals in resource-constrained settings. They should be considered as "core" prognostic factors in future studies that aim at improving the prognosis of VL patients.

A spotlight on the diagnostic methods of a fatal disease Visceral Leishmaniasis.

Leishmania donovani (a causative agent of visceral leishmaniasis) poses a serious health threat to the human population which is fatal if left untreated. The life cycle of Leishmania alternates between vertebrate host and Phlebotomine fly as intermediate ones. Due to the difficulties linked to vector (sandfly) control and the lack of an effective vaccine, the control of leishmaniasis relies mostly on chemotherapy. Unfortunately, the prevalence of parasites becoming resistant to the first-line drug pentavalent antimonial (SbV )/sodium antimony gluconate (SAG) and some other anti-leishmanial drug is increasing in several parts of the world. With the alarming rise of drug resistance and other issues related to VL, there is an urgent need to focus on early detection and quick diagnosis of VL case. Therefore, we have reviewed most of the methods used in the diagnostic process of VL. Along with existing diagnostic methods, developing more effective and sensitive diagnostic methods and biomarkers is also vital for enhancing VL identification and control programs. This review gathers the comprehensive information on diagnostics methods of VL under a single umbrella that could be the prominent tools for the development of rapid, accurate and cost-effective diagnostic kits for VL which can be used in field conditions.

Chlorogenic acid acts upon Leishmania donovani arresting cell cycle and modulating cytokines and nitric oxide in vitro.

AIMS: Visceral leishmaniasis (VL), caused by Leishmania donovani in India, is fatal if untreated, having serious concern of limited chemotherapeutic options. In this study, we evaluated antileishmanial efficacy of purified chlorogenic acid (CGA) against promastigotes and intracellular amastigotes infected into RAW264.7 macrophages. METHODS AND RESULTS: Chlorogenic acid was effective both on promastigotes (IC50  = 78.394 µmol/L, i.e. 27.75 µg/mL) and intracellular amastigotes (ED50  = 26.752 µmol/L, i.e. 9.47 µg/mL). In promastigotes, significant retardation in mitotic growth was caused both by cell-death and reduction of metabolic activity, evidenced by propidium-iodide uptake and MTT assay, respectively. Flow cytometric analysis revealed that retardation of mitotic growth was due to cell-cycle arrest at G1/S checkpoint. Complete clearance of amastigotes from infected RAW264.7 cells, assessed by microscopic counting, was achieved with 60 µmol/L (21.24 µg/mL) CGA for 24 hours, with negligible toxicity to host macrophages. This parasite clearing efficacy was comparable to 1.0 µg/mL (1.082 µmol/L) Amphotericin B, and 20 µmol/L Miltefosine, two standard antileishmanial drugs. Cytokine-ELISA revealed that elevated IL-10 production by infected macrophages was reduced after parasite clearance. Consequently, IL-12, TNF and NO (assayed by Griess test) production by macrophages were significantly increased after successful resolution of infection. CONCLUSION: Chlorogenic acid might emerge as a potential antileishmanial drug.

Risk factors for in-hospital mortality from visceral leishmaniasis: A case-control study.

BACKGROUND: The timely identification of visceral leishmaniasis (VL) patients with a higher risk of death is essential for meeting the target of reducing case-fatality rates in the Americas. This study aimed to identify factors associated with death from VL in the State of Piaui, Brazil. METHODS: Case-control study evaluating the following putative risk factors for death from VL: gender and age of the patient, local of residence, signs, and symptoms, laboratory data, comorbidities and days of evolution of the disease. The associations between risk factors and death were expressed as odds ratios and their respective 95% confidence intervals. RESULTS: In the period analyzed a total of 2525 VL patients were admitted to the hospital, corresponding to 9,3% of all VL admissions in Brazil. Among them, 177 patients died (case-fatality rate of 7.0%). In the multivariate analysis the following variables showed a statistically significant association with death: ≥60 years, vomiting, edema, diarrhea, platelets<50.000/mm³, jaundice, splenomegaly, and pneumonia. CONCLUSIONS: The identified factors associated to death from VL can be easily assessed at the time of or up to 48h after admission and may be used to inform clinical decisions, improving the clinical and laboratory monitoring of patients.

Social determinants of mortality due to visceral leishmaniasis in Brazil (2001-2015): an ecological study

Abstract INTRODUCTION We aimed to analyze the relationship between visceral leishmaniasis mortality and social determinants of health (SDH). METHODS This was an ecological study of all leishmaniasis-related deaths in Brazil, from 2001 to 2015. We analyzed 49 indicators of human development and social vulnerability. The association was tested using the classical and spatial regression model. RESULTS Mortality was associated with indicators that expressed low human development and high social vulnerability: lack of garbage collection, low schooling, unemployment rate, low per capita income, and income inequality (Gini index). CONCLUSIONS: There was an association between high mortality by leishmaniasis and low SDH.

Leishmaniose visceral humana: um retrato da situação de casos em idosos e longevos / Human visceral leishmaniosis: a closure of the situation of cases in elderly and longlived people

Objetivo: analisar a atual situação epidemiológica brasileira e gaúcha da leishmaniose visceral (LVH), em idosos e verificar o coeficiente de letalidade. Métodos: trata-se um estudo transversal realizado com fonte de dados secundária, em consulta à base de dados do Sistema de Informação de Agravos de Notificação (SINAN), de janeiro de 2013 a dezembro de 2017, de casos confirmados de leishmaniose visceral no Brasil e no Rio Grande do Sul, que foram tabulados em Excel e analisados com Epiinfo 7.0. Resultados: casos de LVH em idosos têm aumentado nos últimos 5 anos, dentro do cenário brasileiro e gaúcho. Embora pouco divulgado, é frequente o comprometimento e o aumento da proporção de idosos que vão a óbito pelo LHV, que foi de 20,3% dos casos no período de 2013 a 2017, demonstrando a gravidade da infecção nesse público. Em nosso estudo também encontramos forte relação da idade com o aumento do coeficiente de letalidade, chegando a 46,87% em 2016. Discussão: uma das estratégias recentes no combate à LVH é o abate de cães que contêm o parasita responsável pela transmissão da doença, porém esse método de controle não tem sido muito efetivo. Com isso, constata-se que a medida imunoprofilática, através da vacina Leish-Tec®, tem um efeito favorável no combate à doença somente em animais que não estão em áreas de alta transmissão.

Aims: to analyze the current Brazilian and of the state of Rio Grande do Sul epidemiological situation of visceral leishmaniasis (LVH) in the elderly and verify the mortality coefficient. Methods: This is a cross-sectional study with a secondary data source, taken from SINAN data from January 2013 to December 2017, with confirmed visceral leishmaniasis in Brazil and Rio Grande do Sul, which are tabulated in Excel and analyzed with Epiinfo 7. Results: cases of LVH in the elderly have increased in the last 5 years, within the Brazilian and the state of Rio Grande do Sul settings. Although not widely reported, it is frequent to compromise and increase the proportion of elderly people who die from LVH, which was 20,3% of the cases in the period from 2013 to 2017, demonstrating the seriousness of the infection in this public. In our study we also found a strong relation between age and the increase in the lethality coefficient, reaching 46.87% in 2016. Discussion: One of the recent strategies in the fight against HVL is the slaughter of dogs that contains the parasite responsible for the transmission of the disease, but this method of control has not been very effective. Thus, the immunoprophylactic measurement by Leish-Tec® vaccine has a favorable effect in the fight against the disease only in animals that are not in high transmission areas.

Premature deaths by visceral leishmaniasis in Brazil investigated through a cohort study: A challenging opportunity?

BACKGROUND: Visceral Leishmaniasis (VL) is the most severe form of leishmaniasis because it can lead to death. In the Americas, 96% of cases are in Brazil, and despite efforts, the fatality rate has increased in the past years. We analyzed deaths associated to VL in Brazil and investigated the factors that could influence on the timeliness of fatal outcome with emphasis on time (tStoD). METHODOLOGY: The registered deaths by VL were sourced from the Brazilian National Notification System from 2007-2014. Through a retrospective cohort study, univariate and multivariable Cox proportional hazards model analysis were performed and investigated the factors that could influence the time (tStoD). These factors were analyzed through survival models. RESULTS: Out of the 1,589 reported deaths, the median for onset of the symptoms and the case notification date (tStoN) is 25 days (10-61), and for date of case notification and death (tNotD) is 9 days (4-17). The time (tStoN) to event investigation for HIV non-infected individuals was 1.4 (1.16-1.68) greater than the HIV positive group. At the same time peri-urban and urban area were 0.83 (0.47-1.44) and 1.33 (1.16-1.52), respectively. The explorations revealed apparent differences between the time to event investigation (both for tStoN and tNotD) and the age at the onset of the symptoms. According to the tStoN the rate of notification is 1.73 times greater in patients under 5 years old at the onset of the clinical symptoms compared to older patients. CONCLUSION: VL patients under 5 years old were diagnosed earlier and had shorter survival. It could mean that in younger population, although properly diagnosed, the fatality pattern might be related to the severity of the disease. Main host characteristics were evaluated, and age and co-infections seem to have an impact in the disease progression.

Social determinants of mortality due to visceral leishmaniasis in Brazil (2001-2015): an ecological study.

INTRODUCTION: We aimed to analyze the relationship between visceral leishmaniasis mortality and social determinants of health (SDH). METHODS: This was an ecological study of all leishmaniasis-related deaths in Brazil, from 2001 to 2015. We analyzed 49 indicators of human development and social vulnerability. The association was tested using the classical and spatial regression model. RESULTS: Mortality was associated with indicators that expressed low human development and high social vulnerability: lack of garbage collection, low schooling, unemployment rate, low per capita income, and income inequality (Gini index). CONCLUSIONS: There was an association between high mortality by leishmaniasis and low SDH.

Comorbid infections induce progression of visceral leishmaniasis.

BACKGROUND: Visceral leishmaniasis (VL) is a vector borne zoonotic disease endemic in humans and dogs in Brazil. Due to the increased risk of human infection secondary to the presence of infected dogs, public health measures in Brazil mandate testing and culling of infected dogs. Despite this important relationship between human and canine infection, little is known about what makes the dog reservoir progress to clinical illness, significantly tied to infectiousness to sand flies. Dogs in endemic areas of Brazil are exposed to many tick-borne pathogens, which are likely to alter the immune environment and thus control of L. infantum. RESULTS: A cross-sectional study of 223 dogs from an area of Natal, in the Rio Grande do Norte, Brazil, were studied to determine the association between comorbid tick-borne disease and Leishmania infection in this endemic area. The risk of Leishmania seropositivity was 1.68× greater in dogs with tick-borne disease seropositivity compared to those without (Adjusted RR: 1.68, 95% CI: 1.09-2.61, P = 0.019). A longitudinal study of 214 hunting dogs in the USA was conducted to determine the causal relationship between infection with tick-borne diseases and progression of VL. Hunting dogs were evaluated three times across a full tick season to detect incident infection with tick-borne diseases. A logistic regression model with generalized estimating equations to estimate the parameters was used to determine how exposure to tick-borne disease altered VL progression over these three time points when controlling for other variables. Dogs infected with three or more tick-borne diseases were 11× more likely to be associated with progression to clinical VL than dogs with no tick-borne disease (Adjusted RR: 11.64, 95% CI: 1.22-110.99, P = 0.03). Dogs with exposure to both Leishmania spp. and tick-borne diseases were five times more likely to die during the study period (RR: 4.85, 95% CI: 1.65-14.24, P = 0.0051). CONCLUSIONS: Comorbid tick-borne diseases dramatically increased the likelihood that a dog had clinical L. infantum infection, making them more likely to transmit infection to sand flies and people. As an important consequence, reduction of tick-borne disease exposure through topical or oral insecticides may be an important way to reduce progression and transmissibility of Leishmania infection from the canine reservoir to people.

Treatment outcomes of visceral leishmaniasis in Ethiopia from 2001 to 2017: a systematic review and meta-analysis.

BACKGROUND: Ethiopia has the highest number of visceral leishmaniasis (VL) cases after Sudan in Sub-Saharan Africa. However, there was lack of comprehensive data on VL treatment outcome despite the huge burden of the diseases in the country. Hence, we aimed to perform a systematic review and meta-analysis on this topic to obtain stronger evidence on treatment outcomes of VL from the existing literature in Ethiopia. METHODS: The Cochrane guidelines to conduct meta-analysis following the Preferred Reporting Items for Systematic review and Meta-Analysis statement was used to conduct a computerized systematic search of the PubMed, Google Scholar, and ScienceDirect databases. Random effects model was used to combine studies showing heterogeneity of Cochrane Q P < 0.10 and I2 > 50. Treatment outcomes were assessed at end of treatment and at 6 months follow-up. Subgroup analyses were performed on treatment outcomes based on the different antileishmanial treatment options and patients' HIV status. RESULTS: Fifteen studies were included in the final analyses. At end of treatment, an overall treatment success rate of 82.6% was noticed. At 6 months follow-up, the overall treatment success rate was 72.2%. For patients treated with sodium stibogluconate (SSG), the treatment success rates at the end of treatment and at six-month follow-up were 81.5% and 80.7%, respectively. Multiple doses of liposomal-amphotericin B (L-AMB) had treatment success rates of 96.7 and 71-100% at the end of treatment and at 6 months follow-up, respectively. The combination of SSG with paromomycin (PM) gave treatment success rates of up to 90.1% at the end of treatment. HIV-infected individuals were found to have a higher mortality (odds ratio = 4.77, 95% CI: 1.30-17.43, P = 0.009) rate at 6 months follow-up. CONCLUSIONS: SSG alone has shown lower treatment efficacy in the management of VL when compared to combination of SSG with PM and multiple doses of L-AMB. The combination of SSG with PM gave good treatment success rates with shorter duration of treatment. Hence, the combination of SSG with PM should be used preferentially over SSG monotherapy. Multiple doses of L-AMB showed great efficacy especially among patients with complications, severe disease, HIV co-infection, and intolerance to the adverse effects of antimonials. HIV-infected individuals had a worse prognosis than their HIV-negative counterparts.

Canine visceral leishmaniasis in Araçatuba, state of São Paulo, Brazil, and its relationship with characteristics of dogs and their owners: a cross-sectional and spatial analysis using a geostatistical approach.

BACKGROUND: The incidence of visceral leishmaniasis (VL), one of the most important neglected diseases worldwide, is increasing in Brazil. The objectives of this study were to determine the canine VL (CanL) seroprevalence in an urban area of Araçatuba municipality and to evaluate its relationship with the characteristics of dogs and their owners. RESULTS: The CanL seroprevalence in the study area was 0.081 (95% credible interval [CI]: 0.068-0.096). The following covariates/categories were positively associated with the occurrence of a seropositive dog: more than 10 dogs that had lived in the house (odds ratio [OR] = 2.36; 95% CI: 1.03-5.43) (baseline: 0-10 dogs); house with dogs that previously died of VL (OR = 4.85; 95% CI: 2.65-8.86) or died of causes other than old age (OR = 2.26; 95% CI: 1.12-4.46) (baseline: natural or no deaths); dogs that spent the day in a sheltered backyard (OR = 2.14; 95% CI: 1.05-4.40); dogs that spent the day in an unsheltered backyard or the street (OR = 2.67; 95% CI: 1.28-5.57) (baseline: inside home). Spatial dependence among observations occurred within about 45.7 m. CONCLUSIONS: The number of dogs that had lived in the house, previous deaths by VL or other cause, and the place the dog stayed during the day were associated with the occurrence of a VL seropositive dog. The short-distance spatial dependence could be related to the vector characteristics, producing a local neighbourhood VL transmission pattern. The geostatistical approach in a Bayesian context using integrated nested Laplace approximation (INLA) allowed to identify the covariates associated with VL, including its spatially dependent transmission pattern.

Using focused pharmacovigilance for ensuring patient safety against antileishmanial drugs in Bangladesh's National Kala-azar Elimination Programme.

BACKGROUND: Adverse effects of antileishmanial drugs can affect patients' quality of life and adherence to therapy for visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). In Bangladesh, there are 26 treatment centers that manage leishmaniasis cases coming from 100 endemic upazilas (subdistricts) of 26 districts (these include VL, PKDL, treatment failure, and relapse VL and cutaneous leishmaniasis cases). This study aimed to investigate the feasibility of using focused pharmacovigilance for VL (VLPV) in Bangladesh's National Kala-azar Elimination Programme for the early detection and prevention of expected and unexpected adverse drug reactions (ADRs). METHODS: This activity has been going on since December 2014. Activity area includes secondary public hospital or Upazila health complex (UHC) in hundred sub districts and Surya Kanta Kala-azar Research Center (SKKRC) in Mymensingh District, a specialized center for management of complicated VL and PKDL cases. Communicable Disease Control (CDC) of the Directorate General of Health Services (DGHS) assigned twenty five of hundred UHCs and SKKRC (total 26) as treatment centers depending on their suitable geographical location. This was implemented for better management of VL cases with Liposomal Amphotericin B (AmBisome®) to ensure patient convenience and proper utilization of this expensive donated drug. A VLPV expert committee and a UHC VLPV team were established, an operational manual and pharmacovigilance report forms were developed, training and refresher training of health personnel took place at UHCs and at the central level, collected information such as patient data including demographics, treatment history and response, adverse events were analyzed. This report includes information for the period from December 2014 to December 2016. RESULTS: From December 2014 to December 2016, 1327 leishmaniasis patients were treated and 1066 (80%) were available for VLPV. Out of these, 57, 33, 9, and 1% were new VL, PKDL, VL relapse, and other cases, respectively. Liposomal amphotericin B was mostly used (82%) for case management, followed by miltefosine (20%) and paromomycin (3%). Out of the 1066 patients, 26% experienced ADRs. The most frequent ADR was fever (17%, 176/1066), followed by vomiting (5%, 51/1066). Thirteen serious adverse events (SAEs) (eight deaths and five unexpected SAEs) were observed. The expert committee assessed that three of the deaths and all unexpected SAEs were possibly related to treatment. Out of the five unexpected SAEs, four were miltefosine-induced ophthalmic complications and the other was an AmBisome®-induced avascular necrosis of the nasal alae. The Directorate General of the Drug Administration entered the ADRs into the World Health Organization Uppsala Monitoring Centre (WHO-UMC) VigiFlow database. CONCLUSIONS: This study found that VLPV through NKEP is feasible and should be continued as a routine activity into the public health system of Bangladesh to ensure patient safety against anti-leishmanial drugs.