A framework for assessing and predicting the environmental health impact of infectious diseases: a case study of leptospirosis

This article demonstrates the practical application of an integrated environmental health impact assessment (IEHIA) methodology to investigate an infectious disease (leptospirosis) and the value of using such an approach to estimate future health impact. The assessment described the current health impact (using leptospirosis seroprevalence as a proxy measure) and estimated the future health impact based on scenarios that included indicators of different risk factors. The application of an IEHIA methodology to assess the health impact of an infectious disease was shown to enhance the ability to quantify associations between a disease agent and its health impact by taking into account the environmental drivers of transmission, human behaviour, socioeconomic factors, and the multiple pathways through which exposure and infection could occur

Molecular control of dendritic cell development and function

Dendritic cells (DCs) comprise a distinct lineage of potent antigen-presenting mononuclear phagocytes that serve as both mediators of innate immune responses and key facilitators of the adaptive immune response. DCs play both immunogenic and tolerogenic roles through their dual ability to elicit pathogen-specific T cell immunity as well as induce regulatory T cell (Treg) responses to promote tolerance in the steady state. The aim of the work presented here is to examine the normal regulatory mechanisms of DC development and function, starting with the dissection of mechanisms behind an aberrantly activated developmental pathway, followed by the exploration of new mechanisms governed by two candidate transcription factors. The first chapter of the thesis focuses on the growth factor receptor Flt3, an essential regulator of normal DC development in both mice and humans, and concurrently one of the most commonly mutated proteins found in acute myeloid leukemia (AML). We investigated the effect of its most common activating mutation in AML, the Flt3 internal tandem duplication (Flt3-ITD), and found that this mutation caused a significant cell-intrinsic expansion of all DC populations. This effect was associated with an expansion of Tregs and the ability to dampen self-reactivity, with an inability to control autoimmunity in the absence of Tregs. Thus, we describe a potential mechanism by which leukemia can modulate T cell responses and support Treg expansion indirectly through DCs, which may compromise immunosurveillance and promote leukemogenesis. The subsequent chapters explore the basic molecular mechanisms of DC development by using Flt3 expression as a guide to uncover new candidates involved in the DC transcriptional program. We show that Myc family transcription factor, Mycl1, is largely dispensable for DC development and function, contrary to recent published findings that propose a role in proliferation and T cell priming. On the other hand, we find that conditional deletion of our second candidate gene, an Ets family transcription factor, has diverse effects on DC development, monocyte homeostasis, and cytokine production. Overall, our studies highlight an unexpected molecular link between DC development and leukemogenesis, and elucidate novel mechanisms controlling DC differentiation and function

A systematic review of human and animal leptospirosis in the Pacific Islands reveals pathogen and reservoir diversity

Background The Pacific Islands have environmental conditions highly favourable for transmission of leptospirosis, a neglected zoonosis with highest incidence in the tropics, and Oceania in particular. Recent reports confirm the emergence and outbreaks of leptospirosis in the Pacific Islands, but the epidemiology and drivers of transmission of human and animal leptospirosis are poorly documented, especially in the more isolated and less developed islands. Methodology/Principal findings We conducted a systematic review of human and animal leptospirosis within 25 Pacific Islands (Pls) in Polynesia, Melanesia, Micronesia, as well as Easter Island and Hawaii. We performed a literature search using four international databases for articles published between January 1947 and June 2017. We further included grey literature available on the internet. We identified 148 studies describing leptospirosis epidemiology, but the number of studies varied significantly between Pls. No data were available from four Pls. Human leptospirosis has been reported from 13 Pls, with 63% of all studies conducted in Hawaii, French Polynesia and New Caledonia. Animal leptospirosis has been investigated in 19 Pls and from 14 host species, mainly pigs (18% of studies), cattle (16%) and dogs (11%). Only 13 studies provided information on both human and animal leptospirosis from the same location. Serology results were highly diverse in the region, both in humans and animals. Conclusions/Significance Our study suggests that, as in other tropical regions, leptospirosis is widespread in the Pls while showing some epidemiological heterogeneity. Data are scarce or absent from many Pls. Rodents, cattle, pigs and dogs are all likely to be important carriers, but the relative importance of each animal species in human infection needs to be clarified. Epidemiological surveys with appropriate sampling design, pathogen typing and data analysis are needed to improve our understanding of transmission patterns and to develop effective intervention strategies

The emergence of Leptospira borgpetersenii serovar Arborea in Queensland, Australia, 2001 to 2013

BACKGROUND: Leptospirosis is an emerging infectious disease, with increasing frequency and severity of outbreaks, changing epidemiology of populations at risk, and the emergence of new serovars. Environmental drivers of disease transmission include flooding, urbanisation, poor sanitation, changes in land use and agricultural practices, and socioeconomic factors. In Queensland, human infection with Leptosira borgpetersenii serovar Arborea was first reported in 2001. This study aims to report the emergence of serovar Arborea in Queensland from 2001 to 2013, and investigate potential risk factors for infection and drivers of emergence. METHODS: Data on laboratory-confirmed cases of human leptospirosis in Queensland were obtained from the enhanced surveillance system at the WHO/FAO/OIE Collaborating Centre for Reference and Research on Leptospirosis in Brisbane, Australia. The changing epidemiology of serovar Arborea from 2001 to 2003 was described with respect to case numbers, proportion of leptospirosis cases attributed to the serovar, and geographic distribution. Differences in risk factors for the most common serovars were compared. RESULTS: During this period, 1289 cases of leptospirosis were reported, including 233 cases attributed to serovar Arborea. Risk factors for infection include male gender (91 % of cases), occupation, and recreational exposure. Most common occupations recorded were banana workers (28.4 %), meat workers (7.2 %), dairy farmers (5.8 %), graziers/stockmen (5.5 %), 'other agricultural/rural workers' (16.4 %), and tourists or tourism operators (4.6 %). Time trend analysis showed that while non-Arborea cases decreased over the study period, Arborea cases increased by 3.4 cases per year. The proportion of annual cases attributed to Arborea peaked at 49 % in 2011 after unprecedented flooding in Queensland. Mapping of cases by residential location showed expansion of the geographic range of serovar Arborea, concentrating mostly around Brisbane, Cairns and Innisfail. Serovars varied significantly between ages and occupational groups, and serovar Arborea was most strongly associated with 'other agricultural/rural workers'. CONCLUSIONS: Leptospira borgpetersenii serovar Arborea has been emerging in Queensland since 2001, with increase in case numbers, the proportion of leptospirosis infections attributed to the serovar, as well as expansion of its geographic distribution. Reasons for this emergence are unknown, but climatic factors and environmental change are likely to have played important roles

Drug-free holidays: Compliance, tolerability, and acceptability of a 3-day atovaquone/proguanil schedule for pre-travel malaria chemoprophylaxis in Australian travellers

Background Poor compliance with chemoprophylaxis is a major contributing factor to the risk of malaria in travellers. Pre-travel chemoprophylaxis may improve compliance by enabling ‘drug-free holidays’. The standard treatment dose of atovaquone/proguanil (250mg/100mg, 4 tablets/day for 3 days) provides protection against malaria for at least 4 weeks, and could therefore potentially be used for pre-travel chemoprophylaxis. In this study, we assessed the compliance, tolerability, and acceptability of the 3-day atovaquone/proguanil schedule for malarial chemoprophylaxis. Methods 233 participants were recruited from four specialised travel medicine clinics in Australia. Adults travelling to malaria-endemic areas with low/medium risk for ≤4 weeks were enrolled, and prescribed the 3-day schedule of atovaquone/proguanil, completed at least one day before departure. Questionnaires were used to collect data on demographics, travel destination, medication compliance, side effects, and reasons for choosing the 3-day schedule. The study was registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12616000640404 Results Overall, 97.7% of participants complied with the 3-day schedule. Although side effects were reported in 43.3% of the participants, these were well tolerated, and mainly occurred during the first and second day. None of the participants developed malaria. The main reasons for choosing the 3-day schedule over standard chemoprophylaxis options were that it was easier to remember (72.1%), required taking fewer tablets (54.0%), and to help scientific research (54.0%). Conclusions The 3-day atovaquone/proguanil schedule had an impressively high compliance rate, and was well tolerated and accepted by travellers. Further studies are required to assess the effectiveness of this schedule for chemoprophylaxis in travellers.C. L. L. was supported by a fellowship from the Australian National Health and Medical Research Council (grant number 1109035). This study was conducted as part of everyday clinical practice, and participants or their employers paid for the medications

Modelling lymphatic filariasis elimination in American Samoa: GEOFIL predicts need for new targets and six rounds of mass drug administration

Background: As part of the global effort to eliminate the debilitating mosquito-borne disease lymphatic filariasis (LF), seven rounds of two-drug (diethylcarbamazine and albendazole) mass drug administration (MDA) were conducted in American Samoa over 2000–2006. However subsequent surveys demonstrated ongoing transmission prompting further rounds of three-drug (diethylcarbamazine, albendazole, and ivermectin) MDA starting in 2018. Methods: We extend GEOFIL, a spatially-explicit agent-based model of LF transmission to predict the probability and timing of the local elimination or resurgence of LF for different MDA scenarios starting in 2018: two-drug vs. three-drug MDA, two to seven annual rounds, and population coverage rates of 55–75%. We developed an interactive visualisation comparing the effect of MDA strategies on different outcomes. Results: At least six annual rounds of three-drug MDA treating 75% of the population were required to achieve LF elimination in American Samoa by 2035 in > 50% of simulations. In scenarios where MDA did not achieve elimination, prevalence doubled approximately every three years, even if MDA reduced antigen prevalence to <1% (the target recommended by the World Health Organisation). Prevalence in six- and seven-year-old children was approximately one quarter of the prevalence in the general population. Conclusion: The three rounds of three-drug MDA conducted in 2018, 2019, and 2021 may have come close to WHO targets but are unlikely to interrupt LF transmission in American Samoa without further interventions. The recommended post-MDA surveillance strategy of testing primarily six and seven-year-old children will delay detection of resurgence compared to population representative surveys. The recommended elimination targets (reducing antigen prevalence below 0.5%, 1%, or 2%) may not be sufficient to interrupt transmission in countries with LF epidemiology like American Samoa. Alternative surveillance strategies and interventions designed to identify and eliminate spatially localized residual transmission may need to be considered. Interactive visualisations may assist decision-makers to choose locally appropriate strategies

Lymphatic Filariasis in 2016 in American Samoa: Identifying Clustering and Hotspots Using Non-Spatial and Three Spatial Analytical Methods

Background: American Samoa completed seven rounds of mass drug administration from 2000–2006 as part of the Global Programme to Eliminate Lymphatic Filariasis (LF). However, resurgence was confirmed in 2016 through WHO-recommended school-based transmission assessment survey and a community-based survey. This paper uses data from the 2016 community survey to compare different spatial and non-spatial methods to characterise clustering and hotspots of LF. Method: Non-spatial clustering of infection markers (antigen [Ag], microfilaraemia [Mf], and antibodies (Ab [Wb123, Bm14, Bm33]) was assessed using intra-cluster correlation coefficients (ICC) at household and village levels. Spatial dependence, clustering and hotspots were examined using semivariograms, Kulldorf’s scan statistic and Getis-Ord Gi* statistics based on locations of surveyed households. Results: The survey included 2671 persons (750 households, 730 unique locations in 30 villages). ICCs were higher at household (0.20–0.69) than village levels (0.10–0.30) for all infection markers. Semivariograms identified significant spatial dependency for all markers (range 207–562 metres). Using Kulldorff’s scan statistic, significant spatial clustering was observed in two previously known locations of ongoing transmission: for all markers in Fagali’i and all Abs in Vaitogi. Getis-Ord Gi* statistic identified hotspots of all markers in Fagali’i, Vaitogi, and Pago Pago-Anua areas. A hotspot of Ag and Wb123 Ab was identified around the villages of Nua-Seetaga-Asili. Bm14 and Bm33 Ab hotspots were seen in Maleimi and Vaitogi-Ili’ili-Tafuna. Conclusion: Our study demonstrated the utility of different non-spatial and spatial methods for investigating clustering and hotspots, the benefits of using multiple infection markers, and the value of triangulating results between method

Comparison of immunochromatographic test (ICT) and filariasis test strip (FTS) for detecting lymphatic filariasis antigen in American Samoa, 2016

Circulating filarial antigen (Ag) prevalence, measured using rapid point-of-care tests, is the standard indicator used for monitoring and surveillance in the Global Program to Eliminate Lymphatic Filariasis. In 2015, the immunochromatographic test (ICT) was replaced with the filariasis test strip (FTS), which has higher reported sensitivity. Despite differences in sensitivity, no changes in recommended surveillance targets were made when the FTS was introduced. In 2016, we conducted lymphatic filariasis surveys in American Samoa using FTS, which found higher Ag prevalence than previous surveys that used ICT. To determine whether the increase was real, we assessed the concordance between FTS and ICT results by paired testing of heparinised blood from 179 individuals (63% FTS-positive). ICT had 93.8% sensitivity and 100% specificity for identifying FTS-positive persons, and sensitivity was not associated with age, gender, or presence of microfilariae. Based on these findings, if ICT had been used in the 2016 surveys, the results and interpretation would have been similar to those reported using FTS. American Samoa would have failed Transmission Assessment Survey (TAS) of Grade 1 and 2 children with either test, and community prevalence would not have been significantly different (4.1%, 95% CI, 3.3–4.9% with FTS vs. predicted 3.8%, 95%, CI: 3.1–4.6% with ICT)

GEOFIL: a spatially-explicit agent-based modelling framework for predicting the long-term transmission dynamics of lymphatic filariasis in American Samoa

In this study, a spatially-explicit agent-based modelling framework GEOFIL was developed to predict lymphatic filariasis (LF) transmission dynamics in American Samoa. GEOFIL included individual-level information on age, gender, disease status, household location, household members, workplace/school location and colleagues/schoolmates at each time step during the simulation. In American Samoa, annual mass drug administration from 2000 to 2006 successfully reduced LF prevalence dramatically. However, GEOFIL predicted continual increase in microfilaraemia prevalence in the absence of further intervention. Evidence from seroprevalence and transmission assessment surveys conducted from 2010 to 2016 indicated a resurgence of LF in American Samoa, corroborating GEOFIL’s predictions. The microfilaraemia and antigenaemia prevalence in 6-7-yo children were much lower than in the overall population. Mosquito biting rates were found to be a critical determinant of infection risk. Transmission hotspots are likely to disappear with lower biting rates. GEOFIL highlights current knowledge gaps, such as data on mosquito abundance, biting rates and within-host parasite dynamics, which are important for improving the accuracy of model predictions