Metabolomics Identifies multiple candidate biomarkers to diagnose and stage human African trypanosomiasis

Treatment for human African trypanosomiasis is dependent on the species of trypanosome causing the disease and the stage of the disease (stage 1 defined by parasites being present in blood and lymphatics whilst for stage 2, parasites are found beyond the blood-brain barrier in the cerebrospinal fluid (CSF)). Currently, staging relies upon detecting the very low number of parasites or elevated white blood cell numbers in CSF. Improved staging is desirable, as is the elimination of the need for lumbar puncture. Here we use metabolomics to probe samples of CSF, plasma and urine from 40 Angolan patients infected with Trypanosoma brucei gambiense, at different disease stages. Urine samples provided no robust markers indicative of infection or stage of infection due to inherent variability in urine concentrations. Biomarkers in CSF were able to distinguish patients at stage 1 or advanced stage 2 with absolute specificity. Eleven metabolites clearly distinguished the stage in most patients and two of these (neopterin and 5-hydroxytryptophan) showed 100% specificity and sensitivity between our stage 1 and advanced stage 2 samples. Neopterin is an inflammatory biomarker previously shown in CSF of stage 2 but not stage 1 patients. 5-hydroxytryptophan is an important metabolite in the serotonin synthetic pathway, the key pathway in determining somnolence, thus offering a possible link to the eponymous symptoms of “sleeping sickness”. Plasma also yielded several biomarkers clearly indicative of the presence (87% sensitivity and 95% specificity) and stage of disease (92% sensitivity and 81% specificity). A logistic regression model including these metabolites showed clear separation of patients being either at stage 1 or advanced stage 2 or indeed diseased (both stages) versus control

Strengthening Visceral Leishmaniasis Diagnosis Capacity to Improve Access to Care in Kenya: The Example of Marsabit County

Background: Visceral leishmaniasis (VL), also known as kala-azar, is a neglected tropical disease (NTD) that is fatal if not treated early. The WHO targets the elimination of VL as a public health problem in its 2030 NTD road map. However, improving access to VL diagnosis and treatment remains a major challenge in many VL-endemic countries. Kenya is endemic for VL and is among the top 6 high-disease burden countries in the world. Methods: FIND, through its activities in improving the diagnosis of VL and supporting the elimination of the disease in Kenya, has worked with various county ministries of health (MOH) and central MOH over the last couple of years. FIND’s activities in Marsabit county started in 2018. In this work, we present the implementation of activities and the impacts in Marsabit county. We reviewed the data for 2017 and 2019 outbreaks (before and after the implementation of FIND’s activities) and assessed the importance of improving access and community sensitization to VL diagnosis. We assessed the contribution of each facility to the total distance traveled from a perspective of location optimization. Results: There was a sharp increase in the number of people tested in the 2017 outbreak compared to the 2019 outbreak. In 2017, 437 people were tested compared to 2,338 in 2019. The county reported 234 and 688 VL cases in 2017 and 2019, respectively. The data revealed a shift in the demographic structures of cases toward the younger population (mean age in 2017 was 17.6 years and 15.3 years in 2019), with more female cases reported in 2019 compared to 2017. In 2017, 44.4% were 10 years of age or under. In 2019, the proportion 10 years or below was 52.2%. The addition of two new diagnosis facilities in 2018 resulted in a decrease in the distance traveled by confirmed VL cases from 28.1 km in 2017 to 10.8 km in 2019. Assessing the impact of facility placement indicated the most optimal facilities to provide VL diagnostic services and minimize the distance traveled by patients. Adding new facilities reduces the travel distance until a point where the addition of a new facility provides no additional impact. Conclusion: The results from this study indicate the need to carefully consider the placement of health facilities in improving access to VL diagnosis and treatment and could serve as an investment case in deciding when to stop adding new facilities in a particular setting. Extending the activities in Kenya to other VL-endemic countries in East Africa will contribute significantly toward the elimination of the disease, addressing the needs of marginalized populations and leaving no one behind.Funding for the VL activities in Kenya presented in this paper was provided by the Swiss Agency for Development and Cooperation (SDC) and the Fundación Probitas.S

Assessing the impact of aggregating disease stage data in model predictions of human African trypanosomiasis transmission and control activities in Bandundu province (DRC)

Since the turn of the century, the global community has made great progress towards the elimination of gambiense human African trypanosomiasis (HAT). Elimination programs, primarily relying on screening and treatment campaigns, have also created a rich database of HAT epidemiology. Mathematical models calibrated with these data can help to fill remaining gaps in our understanding of HAT transmission dynamics, including key operational research questions such as whether integrating vector control with current intervention strategies is needed to achieve HAT elimination. Here we explore, via an ensemble of models and simulation studies, how including or not disease stage data, or using more updated data sets affect model predictions of future control strategies

Enabling the Development and Deployment of Next Generation Point-of-Care Diagnostics

<p>Enabling the Development and Deployment of Next Generation Point-of-Care Diagnostics</p

Cerebrospinal fluid neopterin as marker of the meningo-encephalitic stage of Trypanosoma brucei gambiense sleeping sickness.

BACKGROUND: Sleeping sickness, or human African trypanosomiasis (HAT), is a protozoan disease that affects rural communities in sub-Saharan Africa. Determination of the disease stage, essential for correct treatment, represents a key issue in the management of patients. In the present study we evaluated the potential of CXCL10, CXCL13, ICAM-1, VCAM-1, MMP-9, B2MG, neopterin and IgM to complement current methods for staging Trypanosoma brucei gambiense patients. METHODS AND FINDINGS: Five hundred and twelve T. b. gambiense HAT patients originated from Angola, Chad and the Democratic Republic of the Congo (D.R.C.). Their classification as stage 2 (S2) was based on the number of white blood cells (WBC) (>5/µL) or presence of parasites in the cerebrospinal fluid (CSF). The CSF concentration of the eight markers was first measured on a training cohort encompassing 100 patients (44 S1 and 56 S2). IgM and neopterin were the best in discriminating between the two stages of disease with 86.4% and 84.1% specificity respectively, at 100% sensitivity. When a validation cohort (412 patients) was tested, neopterin (14.3 nmol/L) correctly classified 88% of S1 and S2 patients, confirming its high staging power. On this second cohort, neopterin also predicted both the presence of parasites, and of neurological signs, with the same ability as IgM and WBC, the current reference for staging. CONCLUSIONS: This study has demonstrated that neopterin is an excellent biomarker for staging T. b. gambiense HAT patients. A rapid diagnostic test for detecting this metabolite in CSF could help in more accurate stage determination

Assessing Strategies Against Gambiense Sleeping Sickness Through Mathematical Modeling

Background Control of gambiense sleeping sickness relies predominantly on passive and active screening of people, followed by treatment. Methods Mathematical modeling explores the potential of 3 complementary interventions in high- and low-transmission settings. Results Intervention strategies that included vector control are predicted to halt transmission most quickly. Targeted active screening, with better and more focused coverage, and enhanced passive surveillance, with improved access to diagnosis and treatment, are both estimated to avert many new infections but, when used alone, are unlikely to halt transmission before 2030 in high-risk settings. Conclusions There was general model consensus in the ranking of the 3 complementary interventions studied, although with discrepancies between the quantitative predictions due to differing epidemiological assumptions within the models. While these predictions provide generic insights into improving control, the most effective strategy in any situation depends on the specific epidemiology in the region and the associated costs

Aflatoxin B1 levels in groundnut products from local markets in Zambia

In Zambia, groundnut products (milled groundnut powder, groundnut kernels) are mostly sold in under-regulated markets. Coupled with the lack of quality enforcement in such markets, consumers may be at risk to aflatoxin exposure. However, the level of aflatoxin contamination in these products is not known. Compared to groundnut kernels, milled groundnut powder obscures visual indicators of aflatoxin contamination in groundnuts such as moldiness, discoloration, insect damage or kernel damage. A survey was therefore conducted from 2012 to 2014, to estimate and compare aflatoxin levels in these products (n = 202), purchased from markets in important groundnut growing districts and in urban areas. Samples of whole groundnut kernels (n = 163) and milled groundnut powder (n = 39) were analysed for aflatoxin B1 (AFB1) by competitive enzyme-linked immunosorbent assay (cELISA). Results showed substantial AFB1 contamination levels in both types of groundnut products with maximum AFB1 levels of 11,100 μg/kg (groundnut kernels) and 3000 μg/kg (milled groundnut powder). However, paired t test analysis showed that AFB1 contamination levels in milled groundnut powder were not always significantly higher (P > 0.05) than those in groundnut kernels. Even for products from the same vendor, AFB1 levels were not consistently higher in milled groundnut powder than in whole groundnut kernels. This suggests that vendors do not systematically sort out whole groundnut kernels of visually poor quality for milling. However, the overall contamination levels of groundnut products with AFB1 were found to be alarmingly high in all years and locations. Therefore, solutions are needed to reduce aflatoxin levels in such under-regulated markets

Why and where an HIV cure is needed and how it might be achieved

Despite considerable global investment, only 60% of people who live with HIV currently receive antiretroviral therapy. The sustainability of current programmes remains unknown and key incidence rates are declining only modestly. Given the complexities and expenses associated with lifelong medication, developing an effective curative intervention is now a global priority. Here we review why and where a cure is needed, and how it might be achieved. We argue for expanding these efforts from resource-rich regions to sub-Saharan Africa and elsewhere: for any intervention to have an effect, region-specific biological, therapeutic and implementation issues must be addressed