Feasibility of eliminating visceral leishmaniasis from the Indian subcontinent: explorations with a set of deterministic age-structured transmission models

textabstractBackground: Visceral leishmaniasis (VL) is a neglected tropical disease transmitted by sandflies. On the Indian subcontinent (ISC), VL is targeted for elimination as a public health problem by 2017. In the context of VL, the elimination target is defined as an annual VL incidence of <1 per 10,000 capita at (sub-)district level. Interventions focus on vector control, surveillance and on diagnosing and treating VL cases. Many endemic areas have not yet achieved optimal control due to logistical, biological as well as technical challenges. We used mathematical modelling to quantify VL transmission dynamics and predict the feasibility of achieving the VL elimination target with current control strategies under varying assumptions about the reservoir of infection in humans. Methods: We developed three deterministic age-structured transmission models with different main reservoirs of infection in humans: asymptomatic infections (model 1), reactivation of infection after initial infection (model 2), and post kala-azar dermal leishmaniasis (PKDL; model 3). For each model, we defined four sub-variants based on different assumptions about the duration of immunity and age-patterns in exposure to sandflies. All 12 model sub-variants were fitted to data from the KalaNet study in Bihar (India) and Nepal, and the best sub-variant was selected per model. Predictions were made for optimal and sub-optimal indoor residual spraying (IRS) effectiveness for three different levels of VL endemicity. Results: Structurally different models explained the KalaNet data equally well. However, the predicted impact of IRS varied substantially between models, such that a conclusion about reaching the VL elimination targets for the ISC heavily depends on assumptions about the main reservoir of infection in humans: asymptomatic cases, recovered (immune) individuals that reactivate, or PKDL cases. Conclusions: Available data on the impact of IRS so far suggest one model is probably closest to reality (model 1). According to this model, elimination of VL (incidence of <1 per 10,000) by 2017 is only feasible in low and medium endemic settings with optimal IRS. In highly endemic settings and settings with sub-optimal IRS, additional interventions will be required

Challenge of Reducing Perinatal Mortality in Rural Congo: Findings of a Prospective, Population-based Study

Each year, an estimated six million perinatal deaths occur worldwide, and 98% of these deaths occur in lowand middle-income countries. These estimates are based on surveys in both urban and rural areas, and they may underrepresent the problem in rural areas. This study was conducted to quantify perinatal mortality, to identify the associated risk factors, and to determine the most common causes of early neonatal death in a rural area of the Democratic Republic of the Congo (DRC). Data were collected on 1,892 births. Risk factors associated with perinatal deaths were identified using multivariate analysis with logistic regression models. Causes of early neonatal deaths were determined by physician-review of information describing death. The perinatal mortality rate was 61 per 1,000 births; the stillbirth rate was 30 per 1,000 births; and the early neonatal death rate was 32 per 1,000 livebirths. Clinically-relevant factors independently associated with perinatal death included: low birthweight [odds ratio (OR)=13.51, 95% confidence interval (CI) 7.82-23.35], breech presentation (OR)=12.41; 95% CI 4.62-33.33), lack of prenatal care (OR=2.70, 95% CI 1.81-4.02), and parity greater than 4 (OR=1.93 95% CI 1.11-3.37). Over one-half of early neonatal deaths (n=37) occurred during the first two postnatal days, and the most common causes were low birthweight/prematurity (47%), asphyxia (34%), and infection (8%). The high perinatal mortality rate in rural communities in the DRC, approximately one-half of which is attributable to early neonatal death, may be modifiable. Specifically, deaths due to breech presentation, the second most common risk factor, may be reduced by making available emergency obstetric care. Most neonatal deaths occur soon after birth, and nearly three-quarters are caused by low birthweight/prematurity or asphyxia. Neonatal mortality might be reduced by targeting interventions to improve neonatal resuscitation and care of larger preterm infants

Validation of Two Rapid Diagnostic Tests for Visceral Leishmaniasis in Kenya

BACKGROUND: Visceral leishmaniasis (VL) is a systemic parasitic disease that is fatal unless treated. In Kenya, national VL guidelines rely on microscopic examination of spleen aspirate to confirm diagnosis. As this procedure is invasive, it cannot be safely implemented in peripheral health structures, where non-invasive, accurate, easy to use diagnostic tests are needed. METHODOLOGY: We evaluated the sensitivity, specificity and predictive values of two rapid diagnostic tests (RDT), DiaMed IT LEISH and Signal-KA, among consecutive patients with clinical suspicion of VL in two treatment centres located in Baringo and North Pokot District, Rift Valley province, Kenya. Microscopic examination of spleen aspirate was the reference diagnostic standard. Patients were prospectively recruited between May 2010 and July 2011. PRINCIPAL FINDINGS: Of 251 eligible patients, 219 patients were analyzed, including 131 VL and 88 non-VL patients. The median age of VL patients was 16 years with predominance of males (66%). None of the tested VL patients were co-infected with HIV. Sensitivity and specificity of the DiaMed IT LEISH were 89.3% (95%CI: 82.7-94%) and 89.8% (95%CI: 81.5-95.2%), respectively. The Signal KA showed trends towards lower sensitivity (77.1%; 95%CI: 68.9-84%) and higher specificity (95.5%; 95%CI: 88.7-98.7%). Combining the tests did not improve the overall diagnostic performance, as all patients with a positive Signal KA were also positive with the DiaMed IT LEISH. CONCLUSION/SIGNIFICANCE: The DiaMed IT LEISH can be used to diagnose VL in Kenyan peripheral health facilities where microscopic examination of spleen aspirate or sophisticated serological techniques are not feasible. There is a crucial need for an improved RDT for VL diagnosis in East Africa

Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in bihar, India:a retrospective cohort study

Funding: This work was supported by a Clinical PhD Fellowship to MRP (090665) and a Principal Research Fellowship to AHF (079838) from the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Challenge of Reducing Perinatal Mortality in Rural Congo: Findings of a Prospective, Population-based Study

Each year, an estimated six million perinatal deaths occur worldwide, and 98% of these deaths occur in low- and middle-income countries. These estimates are based on surveys in both urban and rural areas, and they may underrepresent the problem in rural areas. This study was conducted to quantify perinatal mortality, to identify the associated risk factors, and to determine the most common causes of early neonatal death in a rural area of the Democratic Republic of the Congo (DRC). Data were collected on 1,892 births. Risk factors associated with perinatal deaths were identified using multivariate analysis with logistic regression models. Causes of early neonatal deaths were determined by physician-review of information describing death. The perinatal mortality rate was 61 per 1,000 births; the stillbirth rate was 30 per 1,000 births; and the early neonatal death rate was 32 per 1,000 livebirths. Clinically-relevant factors independently associated with perinatal death included: low birthweight [odds ratio (OR)=13.51, 95% confidence interval (CI) 7.82-23.35], breech presentation (OR)=12.41; 95% CI 4.62-33.33), lack of prenatal care (OR=2.70, 95% CI 1.81-4.02), and parity greater than 4 (OR=1.93 95% CI 1.11-3.37). Over one-half of early neonatal deaths (n=37) occurred during the first two postnatal days, and the most common causes were low birthweight/prematurity (47%), asphyxia (34%), and infection (8%). The high perinatal mortality rate in rural communities in the DRC, approximately one-half of which is attributable to early neonatal death, may be modifiable. Specifically, deaths due to breech presentation, the second most common risk factor, may be reduced by making available emergency obstetric care. Most neonatal deaths occur soon after birth, and nearly three-quarters are caused by low birthweight/prematurity or asphyxia. Neonatal mortality might be reduced by targeting interventions to improve neonatal resuscitation and care of larger preterm infants

Epidemiology and Clinical Features of Patients with Visceral Leishmaniasis Treated by an MSF Clinic in Bakool Region, Somalia, 2004–2006

Our paper describes the epidemiological features of visceral leishmaniasis in the Bakool region, South Central Somalia, over the years 2004 to 2006. Since 2000, Médecins Sans Frontières has been providing care for patients suffering from visceral leishmaniasis in Huddur, located in a region endemic for visceral leishmaniasis. By the end of 2005, we witnessed a dramatic increase in the number of patients admitted to the Huddur centre with visceral leishmaniasis. In our paper, we provide a description of the profile of patients admitted, thus giving an insight into the epidemiology of visceral leishmaniasis in a part of the world where relatively little has been documented and where the true magnitude of this neglected disease remains unknown

Of cattle, sand flies and men : a systematic review of risk factor analyses for South Asian visceral leishmaniasis and implications for elimination

Background: Studies performed over the past decade have identified fairly consistent epidemiological patterns of risk factors for visceral leishmaniasis (VL) in the Indian subcontinent. Methods and Principal Findings: To inform the current regional VL elimination effort and identify key gaps in knowledge, we performed a systematic review of the literature, with a special emphasis on data regarding the role of cattle because primary risk factor studies have yielded apparently contradictory results. Because humans form the sole infection reservoir, clustering of kala-azar cases is a prominent epidemiological feature, both at the household level and on a larger scale. Subclinical infection also tends to show clustering around kala-azar cases. Within villages, areas become saturated over a period of several years; kala-azar incidence then decreases while neighboring areas see increases. More recently, post kalaazar dermal leishmaniasis (PKDL) cases have followed kala-azar peaks. Mud walls, palpable dampness in houses, and peridomestic vegetation may increase infection risk through enhanced density and prolonged survival of the sand fly vector. Bed net use, sleeping on a cot and indoor residual spraying are generally associated with decreased risk. Poor micronutrient status increases the risk of progression to kala-azar. The presence of cattle is associated with increased risk in some studies and decreased risk in others, reflecting the complexity of the effect of bovines on sand fly abundance, aggregation, feeding behavior and leishmanial infection rates. Poverty is an overarching theme, interacting with individual risk factors on multiple levels. Conclusions: Carefully designed demonstration projects, taking into account the complex web of interconnected risk factors, are needed to provide direct proof of principle for elimination and to identify the most effective maintenance activities to prevent a rapid resurgence when interventions are scaled back. More effective, short-course treatment regimens for PKDL are urgently needed to enable the elimination initiative to succeed

Population Preference of Net Texture prior to Bed Net Trial in Kala-Azar–Endemic Areas

Prior to a community-based efficacy trial of long-lasting insecticidal nets (LLINs) in the prevention of visceral leishmaniasis (VL; also called kala-azar), a pilot study on preference of tools was held in endemic areas of India and Nepal in September 2005

Heterogeneities in leishmania infantum infection : using skin parasite burdens to identify highly infectious dogs

Background: The relationships between heterogeneities in host infection and infectiousness (transmission to arthropod vectors) can provide important insights for disease management. Here, we quantify heterogeneities in Leishmania infantum parasite numbers in reservoir and non-reservoir host populations, and relate this to their infectiousness during natural infection. Tissue parasite number was evaluated as a potential surrogate marker of host transmission potential. Methods: Parasite numbers were measured by qPCR in bone marrow and ear skin biopsies of 82 dogs and 34 crab-eating foxes collected during a longitudinal study in Amazon Brazil, for which previous data was available on infectiousness (by xenodiagnosis) and severity of infection. Results: Parasite numbers were highly aggregated both between samples and between individuals. In dogs, total parasite abundance and relative numbers in ear skin compared to bone marrow increased with the duration and severity of infection. Infectiousness to the sandfly vector was associated with high parasite numbers; parasite number in skin was the best predictor of being infectious. Crab-eating foxes, which typically present asymptomatic infection and are non-infectious, had parasite numbers comparable to those of non-infectious dogs. Conclusions: Skin parasite number provides an indirect marker of infectiousness, and could allow targeted control particularly of highly infectious dogs

Interferon-Gamma Release Assay (Modified QuantiFERON) as a Potential Marker of Infection for Leishmania donovani, a Proof of Concept Study

Visceral leishmaniasis is caused by a parasite of the Leishmania species, but infection does not always lead to overt clinical disease. To detect infection, the Montenegro test or Leishmanin Skin Test (LST) is used along with serological markers. The LST is a test of the delayed-type hypersensitivity response read 48–72 hours after intradermal injection of leishmanin antigen. LST has many drawbacks, as complex administration and reading, boosting of anamnestic immune responses and difficult sourcing of GMP-compliant product and alternative tools for epidemiological research are badly needed. We evaluated whether a Interferon-γ Release Assay based on the QuantiFERON-TB test format, which was approved by the Food and Drug Administration (FDA) as a test for detecting latent Mycobacterium tuberculosis infection, could become an in vitro diagnostic aid for the measurement of cell-mediated immune reactivity against L.donovani. We obtained good results with one of five of the antigens we evaluated and confirm the potential of this assay