Uniting mathematics and biology for control of visceral leishmaniasis

The neglected tropical disease (NTD) visceral leishmaniasis (VL) has been targeted by the WHO for elimination as a public health problem on the Indian subcontinent by 2017 or earlier. To date there is a surprising scarcity of mathematical models capable of capturing VL disease dynamics, which are widely considered central to planning and assessing the efficacy of interventions. The few models that have been developed are examined, highlighting the necessity for better data to parameterise and fit these and future models. In particular, the characterisation and infectiousness of the different disease stages will be crucial to elimination. Modelling can then assist in establishing whether, when, and how the WHO VL elimination targets can be met

Required duration of mass ivermectin treatment for onchocerciasis elimination in Africa: a comparative modelling analysis.

BACKGROUND: The World Health Organization (WHO) has set ambitious targets for the elimination of onchocerciasis by 2020–2025 through mass ivermectin treatment. Two different mathematical models have assessed the feasibility of reaching this goal for different settings and treatment scenarios, namely the individual-based microsimulation model ONCHOSIM and the population-based deterministic model EPIONCHO. In this study, we harmonize some crucial assumptions and compare model predictions on common outputs. METHODS: Using a range of initial endemicity levels and treatment scenarios, we compared the models with respect to the following outcomes: 1) model-predicted trends in microfilarial (mf) prevalence and mean mf intensity during 25 years of (annual or biannual) mass ivermectin treatment; 2) treatment duration needed to bring mf prevalence below a provisional operational threshold for treatment interruption (pOTTIS, i.e. 1.4 %), and 3) treatment duration needed to drive the parasite population to local elimination, even in the absence of further interventions. Local elimination was judged by stochastic fade-out in ONCHOSIM and by reaching transmission breakpoints in EPIONCHO. RESULTS: ONCHOSIM and EPIONCHO both predicted that in mesoendemic areas the pOTTIS can be reached with annual treatment, but that this strategy may be insufficient in very highly hyperendemic areas or would require prolonged continuation of treatment. For the lower endemicity levels explored, ONCHOSIM predicted that the time needed to reach the pOTTIS is longer than that needed to drive the parasite population to elimination, whereas for the higher endemicity levels the opposite was true. In EPIONCHO, the pOTTIS was reached consistently sooner than the breakpoint. CONCLUSIONS: The operational thresholds proposed by APOC may have to be adjusted to adequately reflect differences in pre-control endemicities. Further comparative modelling work will be conducted to better understand the main causes of differences in model-predicted trends. This is a pre-requisite for guiding elimination programmes in Africa and refining operational criteria for stopping mass treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13071-015-1159-9) contains supplementary material, which is available to authorized users

Effects of meteorological factors on epidemic malaria in Ethiopia: a statistical modelling approach based on theoretical reasoning.

This study was conducted to quantify the association between meteorological variables and incidence of Plasmodium falciparum in areas with unstable malaria transmission in Ethiopia. We used morbidity data pertaining to microscopically confirmed cases reported from 35 sites throughout Ethiopia over a period of approximately 6-7 years. A model was developed reflecting biological relationships between meteorological and morbidity variables. A model that included rainfall 2 and 3 months earlier, mean minimum temperature of the previous month and P. falciparum case incidence during the previous month was fitted to morbidity data from the various areas. The model produced similar percentages of over-estimation (19.7% of predictions exceeded twice the observed values) and under-estimation (18.6%, were less than half the observed values). Inclusion of maximum temperature did not improve the model. The model performed better in areas with relatively high or low incidence (>85% of the total variance explained) than those with moderate incidence (55-85% of the total variance explained). The study indicated that a dynamic immunity mechanism is needed in a prediction model. The potential usefulness and drawbacks of the modelling approach in studying the weather-malaria relationship are discussed, including a need for mechanisms that can adequately handle temporal variations in immunity to malaria

Understanding MRSA clonal competition within a UK hospital; the possible importance of density dependence

Background Methicillin resistant Staphylococcus aureus (MRSA) bacteria cause serious, often healthcare-associated infections and are frequently highly resistant to diverse antibiotics. Multiple MRSA clonal complexes (CCs) have evolved independently and countries have different prevalent CCs. It is unclear when and why the dominant CC in a region may switch. Methods We developed a mathematical deterministic model of MRSA CC competing for limited resource. The model distinguishes ‘standard MRSA’ and multidrug resistant sub-populations within each CC, allowing for resistance loss and transfer between same CC bacteria. We first analysed how dynamics of this system depend on growth-rate and resistance-potential differences between CCs, and on their resistance gene accumulation. We then fit the model to capture the longitudinal CC dynamics observed at a single UK hospital, which exemplified the UK-wide switch from mainly CC30 to mainly CC22. Results We find that within a CC, gain and loss of resistance can allow for co-existence of sensitive and resistant sub-populations. Due to more efficient transfer of resistance at higher CC density, more drug resistance can accumulate in the population of a more prevalent CC. We show how this process of density dependent competition, together with prevalence disruption, could explain the relatively sudden switch from mainly CC30 to mainly CC22 in the UK hospital setting. Alternatively, the observed hospital dynamics could be reproduced by assuming that multidrug resistant CC22 evolved only around 2004. Conclusions We showed how higher prevalence may advantage a CC by allowing it to acquire antimicrobial resistances more easily. Due to this density dependence in competition, dominance in an area can depend on historic contingencies; the MRSA CC that happened to be first could stay dominant because of its high prevalence advantage. This then could help explain the stability, despite frequent stochastic introductions across borders, of geographic differences in MRSA CC

What does the COVID-19 pandemic mean for the next decade of onchocerciasis control and elimination?

BACKGROUND: Mass drug administration (MDA) of ivermectin for onchocerciasis has been disrupted by the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modelling can help predict how missed/delayed MDA will affect short-term epidemiological trends and elimination prospects by 2030. METHODS: Two onchocerciasis transmission models (EPIONCHO-IBM and ONCHOSIM) are used to simulate microfilarial prevalence trends, elimination probabilities and age profiles of Onchocerca volvulus microfilarial prevalence and intensity for different treatment histories and transmission settings, assuming no interruption, a 1-y (2020) interruption or a 2-y (2020-2021) interruption. Biannual MDA or increased coverage upon MDA resumption are investigated as remedial strategies. RESULTS: Programmes with shorter MDA histories and settings with high pre-intervention endemicity will be the most affected. Biannual MDA is more effective than increasing coverage for mitigating COVID-19's impact on MDA. Programmes that had already switched to biannual MDA should be minimally affected. In high-transmission settings with short treatment history, a 2-y interruption could lead to increased microfilarial load in children (EPIONCHO-IBM) and adults (ONCHOSIM). CONCLUSIONS: Programmes with shorter (annual MDA) treatment histories should be prioritised for remedial biannual MDA. Increases in microfilarial load could have short- and long-term morbidity and mortality repercussions. These results can guide decision-making to mitigate the impact of COVID-19 on onchocerciasis elimination

Sampling strategies for monitoring and evaluation of morbidity targets for soil-transmitted helminths

Background The current World Health Organization (WHO) target for the three major soil-transmitted helminth (STH) infections is to reduce prevalence of moderate-to-heavy infections to below 1% by 2020. In terms of monitoring and evaluation (M&E), the current WHO guidelines for control of STHs recommend evaluation of infection levels in school-age children (SAC) after five to six years of preventive chemotherapy (PC), using the standard Kato-Katz faecal smear. Here, we assess the predictive performance of various sampling designs for the evaluation of the morbidity target. Methodology/Principal findings Using two mathematical models for STH transmission and control, we simulate how the number of villages and SAC sampled affect the ability of survey results in sentinel villages to predict the achievement of the morbidity target in PC implementation units (e.g. districts). As PC is stopped when the prevalence of infection in SAC in sentinel villages is less than 1%, we estimate the positive predictive value (PPV) of this indicator for meeting the morbidity target in the whole district. The PPV varies by species and PC strategy, and it is generally higher in areas with lower pre-control prevalence. Sampling a fixed number of SAC spread out over 10 instead of 5 sentinel villages may increase the PPV by up to 20 percentage points. If every SAC in a village is tested, a higher number of villages may increase the PPV by up to 80 percentage points. Increasing the proportion of SAC tested per village does not result in a relevant increase of PPV. Conclusions/Significance Although the WHO guidelines provide a combined strategy to control the three STH species, the efficacy of PC strategies clearly differs by species. There is added value in considering more villages within implementation units for M&E of morbidity targets, the extent varying by STH species. A better understanding of pre- and post-control local STH prevalence levels is essential for an adequate M&E strategy including the definition of morbidity targets at the appropriate geographical scale

Cluster randomised trial and development of a sandfly sex pheromone lure to reduce Leishmania infantum infection

Introduction: Vector control tools are needed to combat leishmaniasis. A semi-synthetic version of a Lutzomyia longipalpis aggregation/sex pheromone (9-methlygermacrene-B) has been developed, and shown efficacy to attract sandflies in the lab and to chicken sheds in the field. Here, we present results from a cluster-randomised trial performed in Brazil where we test the efficacy of the pheromone deployed with insecticide, a novel lure-and-kill intervention, to reduce leishmaniasis transmission to the canine reservoir. Aim: Investigate the efficacy of sandfly sex pheromone baited + insecticide treated chicken roosts to reduce transmission of Leishmania infantum among the reservoir population (dogs). Methods: We conducted a cluster-randomised trial across 42 communities in Brazil. Pheromone lures plus insecticide were applied in 14 communities, and outcomes compared to that of 28 other communities that received either a placebo (sham lure + insecticide) or deltamethrin-impregnated collars fitted to dogs. We quantify the primary intervention effects by comparison of the number of uninfected dogs that seroconverted in each arm over the course of the 2-year trial. Results: A reduction in canine incidence is attributed to the pheromone + insecticide intervention, which is consistent across the levels of hierarchical analysis, though the errors are broad. The performance of the pheromone followed similar patterns as the collar arm which significantly reduced seroconversion incidence. Conclusion: These data represent the first trial of a synthetic vector pheromone applied in public health control, and the first cluster-randomised trial of dog collars in Brazil. Both methods show potential for the control of zoonotic visceral leishmaniasis in the Americas; developments of the pheromone lure-and-kill strategy are underway

A cross-sectional study of the prevalence of intensity of infection with Schistosoma japonicum in 50 irrigated and rain-fed villages in Samar Province, the Philippines

BACKGROUND: Few studies have described heterogeneity in Schistosoma japonicum infection intensity, and none were done in Philippines. The purpose of this report is to describe the village-to-village variation in the prevalence of two levels of infection intensity across 50 villages of Samar Province, the Philippines. METHODS: This cross-sectional study was conducted in 25 rain-fed and 25 irrigated villages endemic for S. japonicum between August 2003 and November 2004. Villages were selected based on irrigation and farming criteria. A maximum of 35 eligible households were selected per village. Each participant was asked to provide stool samples on three consecutive days. All those who provided at least one stool sample were included in the analysis. A Bayesian three category outcome hierarchical cumulative logit regression model with adjustment for age, sex, occupation and measurement error of the Kato-Katz technique was used for analysis. RESULTS: A total of 1427 households and 6917 individuals agreed to participate in the study. A total of 5624 (81.3%) participants provided at least one stool sample. The prevalences of those lightly and at least moderately infected varied from 0% (95% Bayesian credible interval (BCI): 0%–3.1%) to 45.2% (95% BCI: 36.5%–53.9%) and 0% to 23.0% (95% BCI: 16.4%–31.2%) from village-to-village, respectively. Using the 0–7 year old group as a reference category, the highest odds ratio (OR) among males and females were that of being aged 17–40-year old (OR = 8.76; 95% BCI: 6.03–12.47) and 11–16-year old (OR = 8.59; 95% BCI: 4.74–14.28), respectively. People who did not work on a rice farm had a lower prevalence of infection than those working full time on a rice farm. The OR for irrigated villages compared to rain-fed villages was 1.41 (95% BCI: 0.50–3.21). DISCUSSION: We found very important village-to-village variation in prevalence of infection intensity. This variation is probably due to village-level variables other than that explained by a crude classification of villages into the irrigated and non-irrigated categories. We are planning to capture this spatial heterogeneity by updating our initial transmission dynamics model with the data reported here combined with 1-year post-treatment follow-up of study participants

Intestinal parasitic infections in schoolchildren in different settings of Côte d'Ivoire : effect of diagnostic approach and implications for control

BACKGROUND: Social-ecological systems govern parasitic infections in humans. Within the frame of assessing the accuracy of a rapid diagnostic test for Schistosoma mansoni in Cote d'Ivoire, three different endemicity settings had to be identified and schoolchildren's intestinal parasitic infection profiles were characterized. METHODS: In September 2010, a rapid screening was conducted in 11 schools in the Azaguie district, south Cote d'Ivoire. In each school, 25 children were examined for S. mansoni and S. haematobium. Based on predefined schistosome endemicity levels, three settings were selected, where schoolchildren aged 8-12 years were asked to provide three stool and three urine samples for an in-depth appraisal of parasitic infections. Triplicate Kato-Katz thick smears were prepared from each stool sample for S. mansoni and soil-transmitted helminth diagnosis, whereas urine samples were subjected to a filtration method for S. haematobium diagnosis. Additionally, a formol-ether concentration method was employed on one stool sample for the diagnosis of helminths and intestinal protozoa. Multivariable logistic regression models were employed to analyse associations between schoolchildren's parasitic infections, age, sex and study setting. RESULTS: The prevalences of S. mansoni and S. haematobium infections in the initial screening ranged from nil to 88% and from nil to 56%, respectively. The rapid screening in the three selected areas revealed prevalences of S. mansoni of 16%, 33% and 78%. Based on a more rigorous diagnostic approach, the respective prevalences increased to 92%, 53% and 33%. S. haematobium prevalences were 0.8%, 4% and 65%. Prevalence and intensity of Schistosoma spp., soil-transmitted helminths and intestinal protozoan infections showed setting-specific patterns. Infections with two or more species concurrently were most common in the rural setting (84%), followed by the peri-urban (28.3%) and urban setting (18.2%). CONCLUSIONS: More sensitive diagnostic tools or rigorous sampling approaches are needed to select endemicity settings with high fidelity. The observed small-scale heterogeneity of helminths and intestinal protozoan infections has important implications for contro

Schistosomiasis transmission at high altitude crater lakes in Western Uganda

<p>Abstract</p> <p>Background</p> <p>Contrary to previous reports which indicated no transmission of schistosomiasis at altitude >1,400 m above sea level in Uganda, in this study it has been established that schistosomiasis transmission can take place at an altitude range of 1487–1682 m above sea level in western Uganda.</p> <p>Methods</p> <p>An epidemiological survey of intestinal schistosomiasis was carried out in school children staying around 13 high altitude crater lakes in Western Uganda. Stool samples were collected and then processed with the Kato-Katz technique using 42 mg templates. Thereafter schistosome eggs were counted under a microscope and eggs per gram (epg) of stool calculated. A semi-structured questionnaire was used to obtain demographic data and information on risk factors.</p> <p>Results</p> <p>36.7% of the pupils studied used crater lakes as the main source of domestic water and the crater lakes studied were at altitude ranging from 1487–1682 m above sea level. 84.6% of the crater lakes studied were infective with over 50% of the users infected.</p> <p>The overall prevalence of <it>Schistosoma mansoni </it>infection was 27.8% (103/370) with stool egg load ranging from 24–6048 per gram of stool. 84.3%( 312) had light infections (<100 eggs/gm of stool), 10.8%( 40) had moderate infections (100–400 eggs/gm of stool) and 4.9% (18) had heavy infections (>400 egg/gm of stool). Prevalence was highest in the age group 12–14 years (49.5%) and geometric mean intensity was highest in the age group 9–11 years (238 epg). The prevalence and geometric mean intensity of infection among girls was lower (26%; 290 epg) compared to that of boys (29.6%; 463 epg) (t = 4.383, p < 0.05). Though 61%(225) of the pupils interviewed were aware of the existence of the disease, 78% (290)didn't know the mode of transmission and only 8% (30) of those found infected were aware of their infection status. In a multivariate logistic regression model, altitude and water source (crater lakes) were significantly associated with infection.</p> <p>Conclusion and recommendations</p> <p>The altitudinal threshold for <it>S. mansoni </it>transmission in Uganda has changed and use of crater water at an altitude higher than 1,400 m above sea level poses a risk of acquiring <it>S. mansoni </it>infection in western Uganda. However, further research is required to establish whether the observed altitudinal threshold change is as a result of climate change or other factors. It is also necessary to establish the impact this could have on the epidemiology of schistosomiasis and other vector-borne diseases in Uganda. In addition, sensitisation and mass treatment of the affected community is urgently required.</p