Comparing antibiotic treatment for leptospirosis using network meta-analysis: a tutorial.

BACKGROUND: Network meta-analysis consists of simultaneous analysis of both direct comparisons of interventions within randomized controlled trials and indirect comparisons across trials based on a common comparator. In this paper, we aimed to characterise the conceptual understanding and the rationale for the use of network meta-analysis in assessing drug efficacy. METHODS: We selected randomized controlled trials, assessing efficacy of antibiotics for the treatment of leptospirosis as a case study. A pairwise meta-analysis was conducted using a random effect model, assuming that different studies assessed different but related treatment effects. The analysis was then extended to a network meta-analysis, which consists of direct and indirect evidence in a network of antibiotics trials, using a suite of multivariate meta-analysis routines of STATA (mvmeta command). We also assessed an assumption of 'consistency' that estimates of treatment effects from direct and indirect evidence are in agreement. RESULTS: Seven randomised controlled trials were identified for this analysis. These RCTs assessed the efficacy of antibiotics such as penicillin, doxycycline and cephalosporin for the treatment of human leptospirosis. These studies made comparisons between antibiotics (i.e. an antibiotic versus alternative antibiotic) in the primary study and a placebo, except for cephalosporin. These studies were sufficient to allow the creation of a network for the network meta-analysis; a closed loop in which three comparator antibiotics were connected to each other through a polygon. The comparison of penicillin versus the placebo has the largest contribution to the entire network (31.8%). The assessment of rank probabilities indicated that penicillin presented the greatest likelihood of improving efficacy among the evaluated antibiotics for treating leptospirosis. CONCLUSIONS: Findings suggest that network meta-analysis, a meta-analysis comparing multiple treatments, is feasible and should be considered as better precision of effect estimates for decisions when several antibiotic options are available for the treatment of leptospirosis.

A process for developing multisectoral strategies for zoonoses: the case of leptospirosis in Fiji.

BACKGROUND: Zoonotic diseases such as leptospirosis occur as a result of the often complex interactions that exist at the human-animal-environment interface. The most obvious consequence of this complexity is the need for the health sector to partner with institutions in other sectors of society such as agriculture, labour and local government. This multisectoral engagement is complicated by the different agendas and cultures of the various institutions and their ability to "see" their role and ant benefits in a collaborative response. METHODS: The research used a realist review methodology combined with systems thinking frameworks to determine the optimal strategy and governance for the prevention and control of leptospirosis in Fiji. The process included facilitated workshops with multiple stakeholders to determine the needs, issues and potential interventions that was guided by a synthesis of locally available data and information on the impact of leptospirosis. This process was informed by interviews with bureaucrats from different government ministries. RESULTS: Stakeholders concurred that leptospirosis generally only received wide-spread attention in outbreaks, when there is media coverage of deaths or a large number of hospitalisations. In general, all ministries expressed support for a multisectoral strategy but saw the Ministry of Health and Medical Services as the lead agency with overall responsibility. The final consultation workshop yielded a clearly articulated goal to reduce the case fatality rate attributable to leptospirosis by 50% by 2020 and 4 overarching strategies: 1) improved clinical management of leptospirosis, 2) improved surveillance for leptospirosis, 3) enhanced communication to minimise risk and improve health seeking behaviours, and 4) strengthening coordination and governance structures. CONCLUSION: Human mortality and morbidity remained the primary drive for government action, defining leptospirosis as a human health problem. The process of deliberative consultation, and the engagement of multidisciplinary partners has provided a platform for collaborative policy development, and a consensus for a National Action Plan from which further negotiated collaboration will be possible.

Comparative pathogenesis of eosinophilic meningitis caused by Angiostrongylus mackerrasae and Angiostrongylus cantonensis in murine and guinea pig models of human infection.

This study investigated comparatively the pathogenicity of experimental infection of mice and guinea pigs, with Angiostrongylus mackerrasae and the closely related species A. cantonensis. Time course analyses showed that A. mackerrasae causes eosinophilic meningitis in these hosts, which suggests that the species has the potential to cause meningitis in humans and domestic animals. Both A. mackerrasae and the genetically similar A. cantonensis caused eosinophilic meningitis in mice at two time points of 14 and 21 days post infection (dpi). The brain lesions in mice infected with A. mackerrasae were more granulomatous in nature and the parasites were more likely to appear degenerate compared with lesions caused by A. cantonensis. This may indicate that the mouse immune system eliminates A. mackerrasae infection more effectively. The immunologic responses of mice infected with the two Angiostrongylus species was compared by assessing ex vivo stimulated spleen derived T cells and cytokines including interferon-gamma, interleukin 4 and interleukin 17 on 14 and 21 dpi. The results were similar for mice infected with A. cantonensis and A. mackerrasae. Serum from the infected animals with either A. cantonensis or A. mackerrasae recognized total soluble antigen of A. cantonensis female worms on Western blot.

Investigation of the morphological diversity of the potentially zoonotic Trypanosoma copemani in quokkas and Gilbert's potoroos.

Trypanosomes are blood-borne parasites that can cause severe disease in both humans and animals, yet little is known of the pathogenicity and life-cycles of trypanosomes in native Australian mammals. Trypanosoma copemani is known to be infective to a variety of Australian marsupials and has recently been shown to be potentially zoonotic as it is resistant to normal human serum. In the present study, in vivo and in vitro examination of blood and cultures from Australian marsupials was conducted using light microscopy, immunofluorescence, scanning electron microscopy and fluorescence in situ hybridization. Promastigote, sphaeromastigote and amastigote life-cycle stages were detected in vivo and in vitro. Novel trypanosome-like stages were also detected both in vivo and in vitro representing an oval stage, an extremely thin stage, an adherent stage and a tiny round stage. The tiny round and adherent stages appeared to adhere to erythrocytes causing potential haematological damage with clinical effects similar to haemolytic anaemia. The present study shows for the first time that trypomastigotes are not the only life-cycle stages circulating within the blood stream of trypanosome infected Australian native marsupials and provides insights into possible pathogenic mechanisms of this potentially zoonotic trypanosome species.

Association of Pesticides and Kidney Function among Adults in the US Population 2001-2010.

Chronic kidney disease of unknown cause is prevalent in a range of communities; however, its etiology remains unclear. We examined the association between pesticide exposures and the risk of kidney function loss using four waves of the National Health and Nutrition Examination Survey (NHANES) to identify a pathological pathway. We pooled data from four cross-sectional waves of NHANES, with 41,847 participants in total. Exposure to malathion increased the risk of low kidney function (aOR = 1.26, 95% CI = 1.01-1.56) in the adjusted model. Increased risk of low kidney function was not found among those exposed to 2,4-D (aOR = 0.88, 95% CI = 0.72-1.09), 3,5,6-trichloropyridinol (aOR = 0.96, 95% CI = 0.83-1.12), and 3-PBA (aOR = 1.03, 95% CI = 0.94-1.13). Our findings provide evidence of altered kidney function in people exposed to malathion, highlighting the potential of organophosphate pesticides' role in renal injury.

Species Traits and Hotspots Associated with Ross River Virus Infection in Nonhuman Vertebrates in South East Queensland.

Ross River virus (RRV) is a mosquito-borne zoonotic arbovirus associated with high public health and economic burdens across Australia, but particularly in South East Queensland (SEQ). Despite this high burden, humans are considered incidental hosts. Transmission of RRV is maintained among mosquitoes and many nonhuman vertebrate reservoir hosts, although the relative contributions of each of these hosts are unclear. To clarify the importance of a range of vertebrates in RRV transmission in SEQ, a total of 595 serum samples from 31 species were examined for RRV exposure using a gold-standard plaque reduction neutralization test. Data were analyzed statistically using generalized linear models and a coefficient inference tree, and spatially. RRV exposure was highly variable between and within species groups. Critically, species group ("placental mammal," "marsupial," and "bird"), which has previously been used as a proxy for reservoir hosts, was a poor correlate for exposure. Instead, we found that generalized "diet" and greater "body mass" were most strongly correlated with seropositivity. We also identified significant differences in seropositivity between the two major possum species (ringtail possums and brushtail possums), which are ecologically and taxonomically different. Finally, we identified distinct hotspots and coldspots of seropositivity in nonhuman vertebrates, which correlated with human notification data. This is the largest diversity of species tested for RRV in a single study to date. The analysis methods within this study provide a framework for analyzing serological data in combination with species traits for other zoonotic disease, but more specifically for RRV highlight areas to target further public health research and surveillance effort.

Clustering of cryptosporidiosis in Queensland, Australia, is not defined temporally or by spatial diversity.

Cryptosporidiosis, caused by infection with Cryptosporidium spp., is a globally distributed disease that manifests as diarrhoea for which there is no effective treatment. The protozoan parasite Cryptosporidium is difficult to detect and control, and can lead to severe disease in young children and the immunocompromised. Individual outbreaks across Australia have predominately been reported in urban areas associated with recreational water, but investigation of spatiotemporal distribution of disease is limited. This study evaluated the spatial and temporal patterns of clusters of notified cases of cryptosporidiosis in the north-eastern Australian state of Queensland, which has the highest average notified cases nationally. A spatiotemporal analysis in SaTScan of 12,263 notified cases from mid 2001 to mid 2015 identified 79 statistically significant disease clusters (P < 0.05). Analyses of annual incidence and disease cluster formation across the state illustrated the substantial randomness of clustering with no clear geographic distribution. Outbreaks were observed temporally across all latitudes and in rural and urban settings, with the majority of clusters centred in major and regional cities. Whilst clusters appeared in areas of high incidence, high incidence itself was not a predictor of clusters. Clusters generally formed during the hottest months between January and April, and cases were primarily children aged 0 to <5 years. Spatiotemporal analysis at a statewide level is an important indicator of regional disease patterns and can act as a trigger for targeted epidemiological investigation.

Q fever vaccine efficacy and occupational exposure risk in Queensland, Australia: A retrospective cohort study.

Q-VAX® is a vaccine used to prevent Q fever. Administration of the vaccine is complicated by the need to ensure, using intradermal and serological tests, that individuals have no prior immunity. Previous studies suggest that the vaccine is highly efficacious and long-lasting in adults. However, there has been no systematic follow-up of vaccine efficacy and the longevity of immunity using population-level data. We aimed to investigate the vaccine failure rate and duration of immunity in previously vaccinated individuals. We formulated a retrospective cohort study design within a linked data. We used a Q fever vaccination registry linked to Q fever notifications and hospital admissions (1991-2016) in the state of Queensland, which has Australia's highest incidence of Q fever. Q-VAX® failure was defined as occurrence of Q fever > 14 days' after vaccination. The incidence of Q fever in vaccinated and unvaccinated individuals was 5.40 (95% CI: 3.65, 7.72) and 89.50 (95% CI: 70.50, 112.00]) per 100,000 person-years of follow-up, respectively. The hazard ratio (HR) for Q fever was 0.07 (95% CI: 0.04, 0.10) in non-immune vaccinated compared with immune unvaccinated individuals. The overall vaccine effectiveness was found to be 94.37% suggesting that Q-VAX® is highly effective at preventing Q fever. However, the greater incidence observed in unvaccinated individuals considered immune during the pre-vaccination screening may suggest that pre-vaccination screening is sub-optimal among this study population.

Associations Between Ross River Virus Infection in Humans and Vector-Vertebrate Community Ecology in Brisbane, Australia.

Transmission of vector-borne pathogens can vary in complexity from single-vector, single-host systems through to multivector, multihost vertebrate systems. Understanding the dynamics of transmission is important for disease prevention efforts, but is dependent on disentangling complex interactions within coupled natural systems. Ross River virus (RRV) is a multivector multihost pathogen responsible for the greatest number of notified vector-borne pathogen infections in humans in Australia. Current evidence suggests that nonhuman vertebrates are critical for the maintenance and spillover of RRV into mosquito populations. Yet, there is a limited knowledge of which mosquito vector species and amplifying vertebrate host species are most important for transmission of RRV to humans. We conducted field surveys of nonhuman vertebrates and mosquitoes in the RRV endemic city of Brisbane, Australia, to assess the effect of vector and host community structure on human RRV notifications. Six suburbs were selected across a gradient of human disease notification rates. Differences in vertebrate and mosquito compositions were observed across all suburbs. Suburbs with higher RRV notification rates contained greater vertebrate biomass (dominated by the presence of horses) and higher mosquito abundances. This study suggests that horse-mosquito interactions should be considered in more detail and that vertebrate biomass and mosquito abundance be incorporated into future RRV modeling studies and considered in public health strategies for RRV management.

Risk factors for human leptospirosis following flooding: A meta-analysis of observational studies.

Leptospirosis is probably the most widespread zoonotic disease in the world especially in tropical countries. There has been an increase in individual studies, which assessed the frequency of leptospirosis in flood conditions. Some studies showed contact with floods was significantly associated with the occurrence of leptospirosis while other studies reported differently. The objective of this meta-analysis was to synthesize the evidence on the risk factors which are associated with human leptospirosis following flooding. We set up the inclusion criteria and searched for the original studies, addressing leptospirosis in human with related to flood in health-related electronic databases including PubMed, Embase, Ovid Medline, google scholar and Scopus sources. We used the terms 'leptospirosis', 'flood', 'risk factor' and terms from the categories were connected with "OR" within each category and by "AND" between categories. The initial search yielded 557 citations. After the title and abstract screening, 49 full-text papers were reviewed and a final of 18 observational studies met the pre-specified inclusion criteria. Overall, the pooled estimates of 14 studies showed that the contact with flooding was a significant factor for the occurrence of leptospirosis (pooled OR: 2.19, 95%CI: 1.48-3.24, I2:86%). On stratification, the strength of association was greater in the case-control studies (pooled OR: 4.01, 95%CI: 1.26-12.72, I2:82%) than other designs (pooled OR:1.77,95%CI:1.18-2.65, I2:87%). Three factors such as 'being male'(pooled OR:2.06, 95%CI:1.29-2.83), the exposure to livestock animals (pooled OR: 1.95, 95%CI:1.26-2.64), the lacerated wound (pooled OR:4.35, 95%CI:3.07-5.64) were the risk factors significantly associated with the incidence of leptospirosis following flooding in the absence of within-study heterogeneity (I2: 0%). We acknowledge study limitations such as publication bias and type 2 statistical errors. We recommended flood control and other environmental modifications that are expected to reduce the risk of leptospiral infection, and a multi-sectoral effort to this aspect would have long-term benefits.

Seroprevlance of Coxiella burnetii among abattoir and slaughterhouse workers: A meta-analysis.

Q fever caused by the gram negative bacteria, Coxiella burnetii, is an occupational hazard for those who live and work in rural settings and those who are in contact with animals, especially abattoir and slaughterhouse workers. Australia is the only country to register a vaccine to prevent Q fever (Q-vax®, Seqirus, Australia) that is used in high risk populations. Seroprevalence studies conducted to determine the burden of Q fever (C. burnetii infection) in different settings have demonstrated high levels of heterogeneity with estimates of the percent positive ranging from 30% to 70%. There is a need for a more systematic evaluation of the findings of these studies in order to provide summary estimates of the seroprevalence in different settings. We searched for published articles using PubMed, MEDLINE-EMBASE, and Scopus databases using search terms obtained from an initial review of published reports of recent Q fever outbreaks. Data on the seroprevalence of C. burnetii infection (Q fever) was extracted from the selected studies and a random effects meta-analysis was performed with stratification by outbreak status, year, country and serological techniques used. Results were visualised with a forest plot with 95% CI and measures of heterogeneity (I 2) for the random effects model. A total of 19 articles that met the search criteria were included. The reported seroprevalence rate ranged from 4.7% to 91.7% among abattoir and slaughterhouse workers. No inter-group heterogeneity was observed (p = 0.956), supporting the pooling of all studies into one pooled measure. The pooled estimate of seropositivity for C. burnetii infection in people working in abattoirs and slaughterhouses was 26% (95% CI: 18-35%) regardless of the evidence of an "outbreak", the time of year or country. Seropositivity for C burnetii was independent of a person's age and years of occupational experience. Within abattoirs and slaughterhouses, slaughtering of cattle, sheep and goats are the most important risk factors associated with seropositivity and for those who showed over symptoms upon infection. We recommend that vaccination programmes are directed towards people employed in the meat processing industry to mitigate the significant health and economic impacts of Q fever.

The non-human reservoirs of Ross River virus: a systematic review of the evidence.

Understanding the non-human reservoirs of zoonotic pathogens is critical for effective disease control, but identifying the relative contributions of the various reservoirs of multi-host pathogens is challenging. For Ross River virus (RRV), knowledge of the transmission dynamics, in particular the role of non-human species, is important. In Australia, RRV accounts for the highest number of human mosquito-borne virus infections. The long held dogma that marsupials are better reservoirs than placental mammals, which are better reservoirs than birds, deserves critical review. We present a review of 50 years of evidence on non-human reservoirs of RRV, which includes experimental infection studies, virus isolation studies and serosurveys. We find that whilst marsupials are competent reservoirs of RRV, there is potential for placental mammals and birds to contribute to transmission dynamics. However, the role of these animals as reservoirs of RRV remains unclear due to fragmented evidence and sampling bias. Future investigations of RRV reservoirs should focus on quantifying complex transmission dynamics across environments.

One Health research and training in Australia and New Zealand.

PURPOSE OF THE REVIEW: This review was performed to create a repository of information on One Health research and training in Australia and New Zealand (ANZ). The review sought to determine 1) how many training activities there are in ANZ, 2) how much research on zoonotic diseases is undertaken by multidisciplinary teams, and 3) how collaborative and integrated they are. RECENT FINDINGS: There are few opportunities for training in One Health in ANZ. The majority require enrolment in a postgraduate degree programme, and there is only one postgraduate level course that is also available for continuing professional development (CPD). Of the broad range of One Health research performed in ANZ, the majority is performed by teams with limited disciplinary diversity, although diversity is improving. SUMMARY: Progress has been made in building collaboration between human, animal, and environmental health professions. However, the lack of clearly defined competencies and agreed purpose for One Health may be impeding collaboration.

Molecular characterization of native Australian trypanosomes in quokka (Setonix brachyurus) populations from Western Australia.

The quokka, Setonix brachyurus, is a vulnerable, small marsupial endemic to Western Australia. Blood samples were collected from quokkas from three different geographical locations; Two Peoples Bay, Bald Island and Rottnest Island. The overall prevalence of trypanosomes by nested PCR at the 18S ribosomal RNA gene was 57.3% (63/110) with prevalences of 91.4%, 85.3% and 4.9% respectively for Two Peoples Bay, Bald Island and Rottnest Island. Phylogenetic analysis conducted on 47 18S PCR positives identified two Trypanosoma copemani genotypes, with T. copemani genotype B, the most prevalent genotype infecting quokka populations from the three locations with an overall prevalence of 51.8% (24/47) compared to 34% for T. copemani genotype A (16/47). The overall prevalence of mixed T. copemani genotype A and B infections was 14.9% (7/47). Phylogenetic analysis of 26 quokka isolates at the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) locus, largely supported the 18S analysis but identified a mixed infection in one quokka isolate (Q4112-4117 from Two Peoples Bay). T. copemani genotype B has previously only been isolated from quokkas and the Gilbert's potoroo whereas T. copemani genotype A has a wide host range and may be pathogenic. Further work is required to determine the clinical impact of T. copemani on marsupial populations.

A survey of Angiostrongylus species in definitive hosts in Queensland.

Despite the recent sporadic reports of angiostrongyliasis in humans, dogs and wildlife in eastern Australia there has been no systematic study to explore the epidemiology of Angiostrongylus spp. in definitive and intermediate hosts in the region. Little is known about the epidemiology of Angiostrongylus species in the definitive host in southeast Queensland, since the only survey conducted in this region was performed in the late 1960s. In this study, free-living populations of Rattus spp. were sampled and examined for the presence of adult and larval Angiostrongylus in the lungs, and of larvae in faeces. The prevalence of infection with Angiostrongylus spp. was 16.5% in Rattus spp. trapped in urban Brisbane and surrounds. This prevalence is much higher than estimates of earlier studies. This highlights the possible risk of zoonotic infection in children, dogs and wildlife in this region and indicates the necessity for public awareness as well as more detailed epidemiological studies on this parasite in eastern Australia.

The mitochondrial genome of Angiostrongylus mackerrasae as a basis for molecular, epidemiological and population genetic studies.

BACKGROUND: Angiostrongylus mackerrasae is a metastrongyloid nematode endemic to Australia, where it infects the native bush rat, Rattus fuscipes. This lungworm has an identical life cycle to that of Angiostrongylus cantonensis, a leading cause of eosinophilic meningitis in humans. The ability of A. mackerrasae to infect non-rodent hosts, specifically the black flying fox, raises concerns as to its zoonotic potential. To date, data on the taxonomy, epidemiology and population genetics of A. mackerrasae are unknown. Here, we describe the mitochondrial (mt) genome of A. mackerrasae with the aim of starting to address these knowledge gaps. METHODS: The complete mitochondrial (mt) genome of A. mackerrasae was amplified from a single morphologically identified adult worm, by long-PCR in two overlapping amplicons (8 kb and 10 kb). The amplicons were sequenced using the MiSeq Illumina platform and annotated using an in-house pipeline. Amino acid sequences inferred from individual protein coding genes of the mt genomes were concatenated and then subjected to phylogenetic analysis using Bayesian inference. RESULTS: The mt genome of A. mackerrasae is 13,640 bp in size and contains 12 protein coding genes (cox1-3, nad1-6, nad4L, atp6 and cob), and two ribosomal RNA (rRNA) and 22 transfer RNA (tRNA) genes. CONCLUSIONS: The mt genome of A. mackerrasae has similar characteristics to those of other Angiostrongylus species. Sequence comparisons reveal that A. mackerrasae is closely related to A. cantonensis and the two sibling species may have recently diverged compared with all other species in the genus with a highly specific host selection. This mt genome will provide a source of genetic markers for explorations of the epidemiology, biology and population genetics of A. mackerrasae.

Emergence of neural angiostrongyliasis in eastern Australia.

Despite an apparent increase in cases of angiostrongyliasis in humans and animals in Australia, the epidemiology of infection with the two species of Angiostrongylus that co-exist in this country, namely A. cantonensis and A. mackerrasae, is poorly understood. This knowledge gap is particularly important with respect to A. mackerrasae, a species evidently native to Australia, as its ability to cause disease in humans is unknown. Likewise, there is little information on the roles of native and introduced species of rodents and molluscs as hosts of Angiostrongylus species in Australia. This review focuses on the gaps in the knowledge about the two species, highlighting the need for epidemiological and pathogenesis studies on the native lungworm A. mackerrasae.

Trypanosoma evansi control and containment in Australasia.

Animal trypanosomosis caused by Trypanosoma evansi is endemic throughout Southeast Asia, where it is an important constraint on the productivity of smallholder livestock. In the past decade, T. evansi has emerged as a serious threat to the viability of smallholder livestock industries in the Philippines and causes severe disease outbreaks with high mortality. Trypanosoma evansi also poses a threat to livestock and native fauna in Australia and Papua New Guinea (PNG) where it is absent, but the risk of it spreading from Indonesia is high. Surveillance for T. evansi in PNG and Australia, and its control in the Philippines is restricted by the poor sensitivity and inadequate validation of existing diagnostic tests and lack of information on the determinants of infection.

Parasites and biosecurity--the example of Australia.

Biosecurity issues as they impact on agriculture, health and the environment are becoming increasingly important. Surveillance is crucial in maintaining a country's biosecurity and this article looks at some of the issues in the context of Australia and its neighbors in the Asia-Pacific region, and emerging threats from parasitic diseases. The important threats to agriculture, public health and wildlife are highlighted, and attention is given to how future surveillance activities must be undertaken on a regional basis and involve neighboring countries if they are to be effective and lead to the protection of both the trade and health of the population.

The seroprevalence and factors associated with Ross river virus infection in western grey kangaroos (Macropus fuliginosus) in Western Australia.

A serosurvey was undertaken in 15 locations in the midwest to southwest of Western Australia (WA) to investigate the seroprevalence of Ross River virus (RRV) neutralizing antibodies and factors associated with infection in western grey kangaroos (Macropus fuliginosus). The estimated seroprevalence in 2632 kangaroo samples, using a serum neutralization test, was 43.9% (95% CI 42.0, 45.8). Location was significantly associated with seroprevalence (p<0.001). There was a strong positive correlation between seroprevalence and the average log-transformed neutralizing antibody titer (r=0.98, p<0.001). The seroprevalence among adult kangaroos was significantly higher than in subadult kangaroos (p<0.05). No significant association was observed between seroprevalence and the sex of kangaroos (p>0.05). The results of this study indicate that kangaroos in WA are regularly infected with RRV and may be involved in the maintenance and transmission of RRV.