- Prevalence, genetic diversity and recombination of species G enteroviruses infecting pigs in Vietnam
Picornaviruses infecting pigs, described for many years as "porcine enteroviruses", have recently been recognised as containing viruses within three distinct genera (Teschovirus, Sapelovirus and Enterovirus). To better characterise the epidemiology and genetic diversity of members of the Enterovirus genus, faecal samples from pigs from four provinces in Vietnam were screened by polymerase chain reaction using conserved enterovirus-specific primers from the 5' untranslated region. High rates of infection were recorded in pigs on all farms, with detection frequencies of approximately 90% in recently weaned pigs but declining to 40% in those aged over one year. No differences in EV detection rates were observed between pigs with and without diarrhoea (74% [n=70] compared with 72% [n=128]). Genetic analysis of consensus VP4/VP2 and VP1 sequences amplified from a subset of EV-infected pigs identified species G EVs in all samples. Among these, VP1 sequence comparisons identified six type 1 and seven type 6 variants while four further VP1 sequences failed to group with any previously identified EV-G types. These have now been formally assigned as EV-G types 8-11 by the Picornavirus Study Group. Comparison of VP1, VP4/VP2, 3Dpol and 5'untranslated regions of study samples and those available on public databases showed frequent, bootstrap supported differences in their phylogenies indicative of extensive within-species recombination between genome regions. In summary, we have identified extremely high frequencies of infection with EV-G in pigs in Vietnam, substantial genetic diversity and recombination within the species and evidence for a much large number of circulating EV-G types than currently described. DOI
- Parasite co-infections and their impact on survival of indigenous cattle
In natural populations, individuals may be infected with multiple distinct pathogens at a time. These pathogens may act independently or interact with each other and the host through various mechanisms, with resultant varying outcomes on host health and survival. To study effects of pathogens and their interactions on host survival, we followed 548 zebu cattle during their first year of life, determining their infection and clinical status every 5 weeks. Using a combination of clinical signs observed before death, laboratory diagnostic test results, gross-lesions on post-mortem examination, histo-pathology results and survival analysis statistical techniques, cause-specific aetiology for each death case were determined, and effect of co-infections in observed mortality patterns. East Coast fever (ECF) caused by protozoan parasite Theileria parva and haemonchosis were the most important diseases associated with calf mortality, together accounting for over half (52%) of all deaths due to infectious diseases. Co-infection with Trypanosoma species increased the hazard for ECF death by 6 times (1.4–25; 95% CI). In addition, the hazard for ECF death was increased in the presence of Strongyle eggs, and this was burden dependent. An increase by 1000 Strongyle eggs per gram of faeces count was associated with a 1.5 times (1.4–1.6; 95% CI) increase in the hazard for ECF mortality. Deaths due to haemonchosis were burden dependent, with a 70% increase in hazard for death for every increase in strongyle eggs per gram count of 1000. These findings have important implications for disease control strategies, suggesting a need to consider co-infections in epidemiological studies as opposed to single-pathogen focus, and benefits of an integrated approach to helminths and East Coast fever disease control. DOI
- The impact of co-infections on the haematological profile of East African Short-horn Zebu calves
The cumulative effect of co-infections between pathogen pairs on the haematological response of East African Short-horn Zebu calves is described. Using a longitudinal study design a stratified clustered random sample of newborn calves were recruited into the Infectious Diseases of East African Livestock (IDEAL) study and monitored at 5-weekly intervals until 51 weeks of age. At each visit samples were collected and analysed to determine the infection status of each calf as well as their haematological response. The haematological parameters investigated included packed cell volume (PCV), white blood cell count (WBC) and platelet count (Plt). The pathogens of interest included tick-borne protozoa and rickettsias, trypanosomes and intestinal parasites. Generalized additive mixed-effect models were used to model the infectious status of pathogens against each haematological parameter, including significant interactions between pathogens. These models were further used to predict the cumulative effect of co-infecting pathogen pairs on each haematological parameter. The most significant decrease in PCV was found with co-infections of trypanosomes and strongyles. Strongyle infections also resulted in a significant decrease in WBC at a high infectious load. Trypanosomes were the major cause of thrombocytopenia. Platelet counts were also affected by interactions between tick-borne pathogens. Interactions between concomitant pathogens were found to complicate the prognosis and clinical presentation of infected calves and should be taken into consideration in any study that investigates disease under field conditions. DOI
- Risk factors for bovine tuberculosis in low incidence regions related to the movements of cattle
Bovine tuberculosis (bTB) remains difficult to eradicate from low incidence regions partly due to the imperfect sensitivity and specificity of routine intradermal tuberculin testing. Herds with unconfirmed reactors that are incorrectly classified as bTB-negative may be at risk of spreading disease, while those that are incorrectly classified as bTB-positive may be subject to costly disease eradication measures. This analysis used data from Scotland in the period leading to Officially Tuberculosis Free recognition (1) to investigate the risks associated with the movements of cattle from herds with different bTB risk classifications and (2) to identify herd demographic characteristics that may aid in the interpretation of tuberculin testing results.
From 2002 to 2009, for every herd with confirmed bTB positive cattle identified through routine herd testing, there was an average of 2.8 herds with at least one unconfirmed positive reactor and 18.9 herds with unconfirmed inconclusive reactors. Approximately 75% of confirmed bTB positive herds were detected through cattle with no known movements outside Scotland. At the animal level, cattle that were purchased from Scottish herds with unconfirmed positive reactors and a recent history importing cattle from endemic bTB regions were significantly more likely to react positively on routine intradermal tuberculin tests, while cattle purchased from Scottish herds with unconfirmed inconclusive reactors were significantly more likely to react inconclusively. Case-case comparisons revealed few demographic differences between herds with confirmed positive, unconfirmed positive, and unconfirmed inconclusive reactors, which highlights the difficulty in determining the true disease status of herds with unconfirmed tuberculin reactors. Overall, the risk of identifying reactors through routine surveillance decreased significantly over time, which may be partly attributable to changes in movement testing regulations and the volume of cattle imported from endemic regions.
Although the most likely source of bTB infections in Scotland was cattle previously imported from endemic regions, we found indirect evidence of transmission within Scottish cattle farms and cannot rule out the possibility of low level transmission between farms. Further investigation is needed to determine whether targeting herds with unconfirmed reactors and a history of importing cattle from high risk regions would benefit control efforts.
- Genetic susceptibility to infectious disease in East African Shorthorn Zebu: a genome-wide analysis of the effect of heterozygosity and exotic introgression
Positive multi-locus heterozygosity-fitness correlations have been observed in a number of natural populations. They have been explained by the correlation between heterozygosity and inbreeding, and the negative effect of inbreeding on fitness (inbreeding depression). Exotic introgression in a locally adapted population has also been found to reduce fitness (outbreeding depression) through the breaking-up of co-adapted genes, or the introduction of non-locally adapted gene variants.
In this study we examined the inter-relationships between genome-wide heterozygosity, introgression, and death or illness as a result of infectious disease in a sample of calves from an indigenous population of East African Shorthorn Zebu (crossbred Bos taurus x Bos indicus) in western Kenya. These calves were observed from birth to one year of age as part of the Infectious Disease in East African Livestock (IDEAL) project. Some of the calves were found to be genetic hybrids, resulting from the recent introgression of European cattle breed(s) into the indigenous population. European cattle are known to be less well adapted to the infectious diseases present in East Africa. If death and illness as a result of infectious disease have a genetic basis within the population, we would expect both a negative association of these outcomes with introgression and a positive association with heterozygosity.
In this indigenous livestock population we observed negative associations between heterozygosity and both death and illness as a result of infectious disease and a positive association between European taurine introgression and episodes of clinical illness.
We observe the effects of both inbreeding and outbreeding depression in the East African Shorthorn Zebu, and therefore find evidence of a genetic component to vulnerability to infectious disease. These results indicate that the significant burden of infectious disease in this population could, in principle, be reduced by altered breeding practices.
- Relative associations of cattle movements, local spread, and biosecurity with bovine viral diarrhoea virus (BVDV) seropositivity in beef and dairy herds
The success of bovine viral diarrhoea virus (BVDV) eradication campaigns can be undermined by spread through local transmission pathways and poor farmer compliance with biosecurity recommendations. This work combines recent survey data with cattle movement data to explore the issues likely to impact on the success of BVDV control in Scotland. In this analysis, data from 249 beef suckler herds and 185 dairy herds in Scotland were studied retrospectively to determine the relative influence of cattle movements, local spread, and biosecurity on BVDV seropositivity. Multivariable logistic regression models revealed that cattle movement risk factors had approximately 3 times greater explanatory power than risk factors for local spread amongst beef suckler herds, but approximately the same explanatory power as risk factors for local spread amongst dairy herds. These findings are most likely related to differences in cattle husbandry practices and suggest that where financial prioritization is required, focusing on reducing movement-based risk is likely to be of greatest benefit when applied to beef suckler herds. The reported use of biosecurity measures such as purchasing cattle from BVDV accredited herds only, performing diagnostic screening at the time of sale, implementing isolation periods for purchased cattle, and installing double fencing on shared field boundaries had minimal impact on the risk of beef or dairy herds being seropositive for BVDV. Only 28% of beef farmers and 24% of dairy farmers with seropositive herds recognized that their cattle were affected by BVDV and those that did perceive a problem were no less likely to sell animals as replacement breeding stock and no more likely to implement biosecurity measures against local spread than farmers with no perceived problems. In relation to the current legislative framework for BVDV control in Scotland, these findings emphasize the importance of requiring infected herds take appropriate biosecurity measures to prevent further disease transmission and conducting adequate follow-up to ensure that biosecurity measures are being implemented correctly in the field. DOI
- Reconstructing Geographical Movements and Host Species Transitions of Foot-and-Mouth Disease Virus Serotype SAT 2
ABSTRACT Of the three foot-and-mouth-disease virus SAT serotypes mainly confined to sub-Saharan Africa, SAT 2 is the strain most often recorded in domestic animals and has caused outbreaks in North Africa and the Middle East six times in the last 25 years, with three apparently separate events occurring in 2012. This study updates the picture of SAT 2 phylogenetics by using all available sequences for the VP1 section of the genome available at the time of writing and uses phylogeographic methods to trace the origin of all outbreaks occurring north of the Sahara since 1990 and identify patterns of spread among countries of endemicity. Transitions between different host species are also enumerated. Outbreaks in North Africa appear to have origins in countries immediately south of the Sahara, whereas those in the Middle East are more often from East Africa. The results of the analysis of spread within sub-Saharan Africa are consistent with it being driven by relatively short-distance movements of animals across national borders, and the analysis of host species transitions supports the role of the African buffalo (Syncerus caffer) as an important natural reservoir. IMPORTANCE Foot-and-mouth disease virus is a livestock pathogen of major economic importance, with seven distinct serotypes occurring globally. The SAT 2 serotype, endemic in sub-Saharan Africa, has caused a number of outbreaks in North Africa and the Middle East during the last decades, including three separate incidents in 2012. A comprehensive analysis of all available RNA sequences for SAT 2 has not been published for some years. In this work, we performed this analysis using all previously published sequences and 49 newly determined examples. We also used phylogenetic methods to infer the source country for all outbreaks occurring outside sub-Saharan Africa since 1990 and to reconstruct the spread of viral lineages between countries where it is endemic and movements between different host species. DOI
- The performance of approximations of farm contiguity compared to contiguity defined using detailed geographical information in two sample areas in Scotland: implications for foot-and-mouth disease modelling
Background: When modelling infectious diseases, accurately capturing the pattern of dissemination through space is key to providing optimal recommendations for control. Mathematical models of disease spread in livestock, such as for foot-and-mouth disease (FMD), have done this by incorporating a transmission kernel which describes the decay in transmission rate with increasing Euclidean distance from an infected premises (IP). However, this assumes a homogenous landscape, and is based on the distance between point locations of farms. Indeed, underlying the spatial pattern of spread are the contact networks involved in transmission. Accordingly, area-weighted tessellation around farm point locations has been used to approximate field-contiguity and simulate the effect of contiguous premises (CP) culling for FMD. Here, geographic data were used to determine contiguity based on distance between premises' fields and presence of landscape features for two sample areas in Scotland. Sensitivity, positive predictive value, and the True Skill Statistic (TSS) were calculated to determine how point distance measures and area-weighted tessellation compared to the 'gold standard' of the map-based measures in identifying CPs. In addition, the mean degree and density of the different contact networks were calculated.
Results: Utilising point distances <1 km and <5 km as a measure for contiguity resulted in poor discrimination between map-based CPs/non-CPs (TSS 0.279-0.344 and 0.385-0.400, respectively). Point distance <1 km missed a high proportion of map-based CPs; <5 km point distance picked up a high proportion of map-based non-CPs as CPs. Area-weighted tessellation performed best, with reasonable discrimination between map-based CPs/ non-CPs (TSS 0.617-0.737) and comparable mean degree and density. Landscape features altered network properties considerably when taken into account.
Conclusion: The farming landscape is not homogeneous. Basing contiguity on geographic locations of field boundaries and including landscape features known to affect transmission into FMD models are likely to improve individual farm-level accuracy of spatial predictions in the event of future outbreaks. If a substantial proportion of FMD transmission events are by contiguous spread, and CPs should be assigned an elevated relative transmission rate, the shape of the kernel could be significantly altered since ability to discriminate between map-based CPs and non-CPs is different over different Euclidean distances.DOI
- Vaccination against Foot-And-Mouth Disease: Do Initial Conditions Affect Its Benefit?
When facing incursion of a major livestock infectious disease, the decision to implement a vaccination programme is made at the national level. To make this decision, governments must consider whether the benefits of vaccination are sufficient to outweigh potential additional costs, including further trade restrictions that may be imposed due to the implementation of vaccination. However, little consensus exists on the factors triggering its implementation on the field. This work explores the effect of several triggers in the implementation of a reactive vaccination-to-live policy when facing epidemics of foot-and-mouth disease. In particular, we tested whether changes in the location of the incursion and the delay of implementation would affect the epidemiological benefit of such a policy in the context of Scotland. To reach this goal, we used a spatial, premises-based model that has been extensively used to investigate the effectiveness of mitigation procedures in Great Britain. The results show that the decision to vaccinate, or not, is not straightforward and strongly depends on the underlying local structure of the population-at-risk. With regards to disease incursion preparedness, simply identifying areas of highest population density may not capture all complexities that may influence the spread of disease as well as the benefit of implementing vaccination. However, if a decision to vaccinate is made, we show that delaying its implementation in the field may markedly reduce its benefit. This work provides guidelines to support policy makers in their decision to implement, or not, a vaccination-to-live policy when facing epidemics of infectious livestock disease. DOI
- Predicting the public health benefit of vaccinating cattle against Escherichia coli O157
Identifying the major sources of risk in disease transmission is key to designing effective controls. However, understanding of transmission dynamics across species boundaries is typically poor, making the design and evaluation of controls particularly challenging for zoonotic pathogens. One such global pathogen is Escherichia coli O157, which causes a serious and sometimes fatal gastrointestinal illness. Cattle are the main reservoir for E. coli O157, and vaccines for cattle now exist. However, adoption of vaccines is being delayed by conflicting responsibilities of veterinary and public health agencies, economic drivers, and because clinical trials cannot easily test interventions across species boundaries, lack of information on the public health benefits. Here, we examine transmission risk across the cattle-human species boundary and show three key results. First, supershedding of the pathogen by cattle is associated with the genetic marker stx2. Second, by quantifying the link between shedding density in cattle and human risk, we show that only the relatively rare supershedding events contribute significantly to human risk. Third, we show that this finding has profound consequences for the public health benefits of the cattle vaccine. A naïve evaluation based on efficacy in cattle would suggest a 50% reduction in risk; however, because the vaccine targets the major source of human risk, we predict a reduction in human cases of nearly 85%. By accounting for nonlinearities in transmission across the human-animal interface, we show that adoption of these vaccines by the livestock industry could prevent substantial numbers of human E. coli O157 cases. DOI
- Ecological and taxonomic variation among human RNA viruses
Only a minority of RNA viruses that can infect humans are capable of spreading in human populations independently of a zoonotic reservoir. This is especially true of vector-borne RNA viruses; the majority of these are not transmissible (via the vector) between humans at all. Understanding the biology underlying this observation will help us evaluate the public health risk associated with novel vector-borne RNA viruses. DOI
- Microbiology. Sources of antimicrobial resistance
- Mortality in East African shorthorn zebu cattle under one year: predictors of infectious-disease mortality
Infectious livestock diseases remain a major threat to attaining food security and are a source of economic and livelihood losses for people dependent on livestock for their livelihood. Knowledge of the vital infectious diseases that account for the majority of deaths is crucial in determining disease control strategies and in the allocation of limited funds available for disease control. Here we have estimated the mortality rates in zebu cattle raised in a smallholder mixed farming system during their first year of life, identified the periods of increased risk of death and the risk factors for calf mortality, and through analysis of post-mortem data, determined the aetiologies of calf mortality in this population. A longitudinal cohort study of 548 zebu cattle was conducted between 2007 and 2010. Each calf was followed during its first year of life or until lost from the study. Calves were randomly selected from 20 sub-locations and recruited within a week of birth from different farms over a 45 km radius area centered on Busia in the Western part of Kenya. The data comprised of 481.1 calf years of observation. Clinical examinations, sample collection and analysis were carried out at 5 week intervals, from birth until one year old. Cox proportional hazard models with frailty terms were used for the statistical analysis of risk factors. A standardized post-mortem examination was conducted on all animals that died during the study and appropriate samples collected. DOI
- Parasite co-infections show synergistic and antagonistic interactions on growth performance of East African zebu cattle under one year
SUMMARY The co-occurrence of different pathogen species and their simultaneous infection of hosts are common, and may affect host health outcomes. Co-infecting pathogens may interact synergistically (harming the host more) or antagonistically (harming the host less) compared with single infections. Here we have tested associations of infections and their co-infections with variation in growth rate using a subset of 455 animals of the Infectious Diseases of East Africa Livestock (IDEAL) cohort study surviving to one year. Data on live body weight, infections with helminth parasites and haemoparasites were collected every 5 weeks during the first year of life. Growth of zebu cattle during the first year of life was best described by a linear growth function. A large variation in daily weight gain with a range of 0·03-0·34 kg, and a mean of 0·135 kg (0·124, 0·146; 95% CI) was observed. After controlling for other significant covariates in mixed effects statistical models, the results revealed synergistic interactions (lower growth rates) with Theileria parva and Anaplasma marginale co-infections, and antagonistic interactions (relatively higher growth rates) with T. parva and Theileria mutans co-infections, compared with infections with T. parva only. Additionally, helminth infections can have a strong negative effect on the growth rates but this is burden-dependent, accounting for up to 30% decrease in growth rate in heavily infected animals. These findings present evidence of pathogen-pathogen interactions affecting host growth, and we discuss possible mechanisms that may explain observed directions of interactions as well as possible modifications to disease control strategies when co-infections are present. DOI
- Maternal antibody uptake, duration and influence on survival and growth rate in a cohort of indigenous calves in a smallholder farming system in western Kenya
The passive transfer of antibodies from dams to offspring via colostrum is believed to play an important role in protecting neonatal mammals from infectious disease. The study presented here investigates the uptake of colostrum by 548 calves in western Kenya maintained under smallholder farming, an important agricultural system in eastern Africa. Serum samples collected from the calves and dams at recruitment (within the first week of life) were analysed for the presence of antibodies to four tick-borne haemoparasites: Anaplasma marginale, Babesia bigemina, Theileria mutans and Theileria parva. The analysis showed that at least 89.33% of dams were seropositive for at least one of the parasites, and that 93.08% of calves for which unequivocal results were available showed evidence of having received colostrum. The maternal antibody was detected up until 21 weeks of age in the calves. Surprisingly, there was no discernible difference in mortality or growth rate between calves that had taken colostrum and those that had not. The results are also important for interpretation of serosurveys of young calves following natural infection or vaccination. DOI
- Design and descriptive epidemiology of the Infectious Diseases of East African Livestock (IDEAL) project, a longitudinal calf cohort study in western Kenya
There is a widely recognised lack of baseline epidemiological data on the dynamics and impacts of infectious cattle diseases in east Africa. The Infectious Diseases of East African Livestock (IDEAL) project is an epidemiological study of cattle health in western Kenya with the aim of providing baseline epidemiological data, investigating the impact of different infections on key responses such as growth, mortality and morbidity, the additive and/or multiplicative effects of co-infections, and the influence of management and genetic factors. A longitudinal cohort study of newborn calves was conducted in western Kenya between 2007-2009. Calves were randomly selected from all those reported in a 2 stage clustered sampling strategy. Calves were recruited between 3 and 7 days old. A team of veterinarians and animal health assistants carried out 5-weekly, clinical and postmortem visits. Blood and tissue samples were collected in association with all visits and screened using a range of laboratory based diagnostic methods for over 100 different pathogens or infectious exposures.
The study followed the 548 calves over the first 51 weeks of life or until death and when they were reported clinically ill. The cohort experienced a high all cause mortality rate of 16% with at least 13% of these due to infectious diseases. Only 307 (6%) of routine visits were classified as clinical episodes, with a further 216 reported by farmers. 54% of calves reached one year without a reported clinical episode. Mortality was mainly to east coast fever, haemonchosis, and heartwater. Over 50 pathogens were detected in this population with exposure to a further 6 viruses and bacteria.
The IDEAL study has demonstrated that it is possible to mount population based longitudinal animal studies. The results quantify for the first time in an animal population the high diversity of pathogens a population may have to deal with and the levels of co-infections with key pathogens such as Theileria parva. This study highlights the need to develop new systems based approaches to study pathogens in their natural settings to understand the impacts of co-infections on clinical outcomes and to develop new evidence based interventions that are relevant. DOI
- Society should decide on UK badger cull
- Vaccination and reduced cohort duration can drive virulence evolution: marek's disease virus and industrialized agriculture
Marek's disease virus (MDV), a commercially important disease of poultry, has become substantially more virulent over the last 60 years. This evolution was presumably a consequence of changes in virus ecology associated with the intensification of the poultry industry. Here, we assess whether vaccination or reduced host life span could have generated natural selection, which favored more virulent strains. Using previously published experimental data, we estimated viral fitness under a range of cohort durations and vaccine treatments on broiler farms. We found that viral fitness maximized at intermediate virulence, as a result of a trade-off between virulence and transmission previously reported. Our results suggest that vaccination, acting on this trade-off, could have led to the evolution of increased virulence. By keeping the host alive, vaccination prolongs infectious periods of virulent strains. Improvements in host genetics and nutrition, which reduced broiler life spans below 50 days, could have also increased the virulence of the circulating MDV strains because shortened cohort duration reduces the impact of host death on viral fitness. These results illustrate the dramatic impact anthropogenic change can potentially have on pathogen virulence. DOI
- The diversity of human RNA viruses
We still cannot answer the very basic question 'how many kinds of RNA viruses are there?' even for those that infect humans. It is often suggested that there remains a large number of viruses in humans that we have not yet discovered or recognized, and that there is a much larger and rapidly evolving pool of potential new viruses in mammalian and avian reservoirs that humans are continually being exposed to. However, a careful examination of discovery rates of new human RNA virus species, genera and families challenges this view, raising the possibility that this diversity is much more limited. Moreover, there is some evidence that the cast of human viruses is dynamic, with existing viruses disappearing (at least from humans) and new viruses appearing (perhaps evolving) over timescales of decades. Most of these new viruses, however, remain rare; only a small (but highly significant) minority are capable of spreading extensively through human populations.DOI
- Impact of changes in cattle movement regulations on the risks of bovine tuberculosis for Scottish farms
Legislation requiring the pre- and post-movement testing of cattle imported to Scotland from regions with high bovine tuberculosis (bTB) incidence was phased in between September 2005 and May 2006 as part of efforts to maintain Officially Tuberculosis Free (OTF) status. In this analysis, we used centralized cattle movement records to investigate the influence of the legislative change on import movement patterns and the movement-based risk factors associated with new bTB herd breakdowns identified through routine testing or slaughter surveillance. The immediate reduction in the number of import movements from high incidence regions of England and Wales into Scotland suggests that pre- and post-movement testing legislation has had a strong deterrent effect on cattle import trade. Combined with the direct benefits of a more stringent testing regime, this likely explains the observed decrease in the odds of imported cattle subsequently being identified as reactors in herd breakdowns detected through routine surveillance compared to Scottish cattle. However, at the farm-level, herds that recently imported cattle from high incidence regions were still at increased risk of experiencing bTB breakdowns, which highlights the delay between the introduction of disease control measures and detectable changes in incidence. With the relative infrequency of routine herd tests and the insidious nature of clinical signs, past import movements were likely still important in determining the present farm-level risk for bTB breakdown. However, the possibility of low-level transmission between Scottish cattle herds cannot be ruled out given the known issues with test sensitivity, changes in import animal demographics, and the potential for on-farm transmission. Findings from this analysis emphasize the importance of considering how farmer behavioural change in response to policy interventions may influence disease transmission dynamics. DOI
- Understanding foot-and-mouth disease virus transmission biology: identification of the indicators of infectiousness
The control of foot-and-mouth disease virus (FMDV) outbreaks in non-endemic countries relies on the rapid detection and removal of infected animals. In this paper we use the observed relationship between the onset of clinical signs and direct contact transmission of FMDV to identify predictors for the onset of clinical signs and identify possible approaches to preclinical screening in the field. Threshold levels for various virological and immunological variables were determined using Receiver Operating Characteristic (ROC) curve analysis and then tested using generalized linear mixed models to determine their ability to predict the onset of clinical signs. In addition, concordance statistics between qualitative real time PCR test results and virus isolation results were evaluated. For the majority of animals (71%), the onset of clinical signs occurred 3--4 days post infection. The onset of clinical signs was associated with high levels of virus in the blood, oropharyngeal fluid and nasal fluid. Virus is first detectable in the oropharyngeal fluid, but detection of virus in the blood and nasal fluid may also be good candidates for preclinical indicators. Detection of virus in the air was also significantly associated with transmission. This study is the first to identify statistically significant indicators of infectiousness for FMDV at defined time periods during disease progression in a natural host species. Identifying factors associated with infectiousness will advance our understanding of transmission mechanisms and refine intra-herd and inter-herd disease transmission models. DOI
- Bluetongue and Epizootic Haemorrhagic Disease virus in local breeds of cattle in Kenya
The presence of bluetongue virus (BTV) and Epizootic Haemorrhagic Disease virus (EHDV) in indigenous calves in western Kenya was investigated. Serum was analysed for BTV and EHDV antibodies. The population seroprevalences for BTV and EHDV for calves at 51weeks of age were estimated to be 0.942 (95% CI 0.902-0.970) and 0.637 (95% CI 0.562-0.710), respectively, indicating high levels of circulating BTV and EHDV. The odds ratio of being positive for BTV if EHDV positive was estimated to be 2.57 (95% CI 1.37-4.76). When 99 calves were tested for BTV and EHDV RNA by real-time RT-PCR, 88.9% and 63.6% were positive, respectively. Comparison of the serology and real-time RT-PCR results revealed an unexpectedly large number of calves that were negative by serology but positive by real-time RT-PCR for EHDV. Eight samples positive for BTV RNA were serotyped using 24 serotype-specific real-time RT-PCR assays. Nine BTV serotypes were detected, indicating that the cattle were infected with a heterogeneous population of BTVs. The results show that BTV and EHDV are highly prevalent, with cattle being infected from an early age. DOI
- Prediction and prevention of the next pandemic zoonosis
Most pandemics-eg, HIV/AIDS, severe acute respiratory syndrome, pandemic influenza-originate in animals, are caused by viruses, and are driven to emerge by ecological, behavioural, or socioeconomic changes. Despite their substantial effects on global public health and growing understanding of the process by which they emerge, no pandemic has been predicted before infecting human beings. We review what is known about the pathogens that emerge, the hosts that they originate in, and the factors that drive their emergence. We discuss challenges to their control and new efforts to predict pandemics, target surveillance to the most crucial interfaces, and identify prevention strategies. New mathematical modelling, diagnostic, communications, and informatics technologies can identify and report hitherto unknown microbes in other species, and thus new risk assessment approaches are needed to identify microbes most likely to cause human disease. We lay out a series of research and surveillance opportunities and goals that could help to overcome these challenges and move the global pandemic strategy from response to pre-emption.DOI
- Disease transmission on fragmented contact networks: Livestock-associated Methicillin-resistant Staphylococcus aureus in the Danish pig-industry
Animal trade in industrialised livestock-production systems creates a complex, heterogeneous, contact network that shapes between-herd transmission of infectious diseases. We report the results of a simple mathematical model that explores patterns of spread and persistence of livestock-associated Methicillin-resistant Staphylococcus aureus (LA-MRSA) in the Danish pig-industry associated with this trade network. Simulations show that LA-MRSA can become endemic sustained by animal movements alone. Despite the extremely low predicted endemic prevalence, eradication may be difficult, and decreasing within-farm prevalence, or the time it takes a LA-MRSA positive farm to recover a negative status, fails to break long-term persistence. Our results suggest that a low level of non-movement induced transmission strongly affects MRSA dynamics, increasing endemic prevalence and probability of persistence. We also compare the model-predicted risk of 291 individual farms becoming MRSA positive, with results from a recent Europe-wide survey of LA-MRSA in holdings with breeding pigs, and find a significant correlation between contact-network connectivity properties and the model-estimated risk measure.DOI
- Human viruses: discovery and emergence
There are 219 virus species that are known to be able to infect humans. The first of these to be discovered was yellow fever virus in 1901, and three to four new species are still being found every year. Extrapolation of the discovery curve suggests that there is still a substantial pool of undiscovered human virus species, although an apparent slow-down in the rate of discovery of species from different families may indicate bounds to the potential range of diversity. More than two-thirds of human viruses can also infect non-human hosts, mainly mammals, and sometimes birds. Many specialist human viruses also have mammalian or avian origins. Indeed, a substantial proportion of mammalian viruses may be capable of crossing the species barrier into humans, although only around half of these are capable of being transmitted by humans and around half again of transmitting well enough to cause major outbreaks. A few possible predictors of species jumps can be identified, including the use of phylogenetically conserved cell receptors. It seems almost inevitable that new human viruses will continue to emerge, mainly from other mammals and birds, for the foreseeable future. For this reason, an effective global surveillance system for novel viruses is needed.DOI
- Protective immunity to Schistosoma haematobium infection is primarily an anti-fecundity response stimulated by the death of adult worms
Protective immunity against human schistosome infection develops slowly, for reasons that are not yet fully understood. For many decades, researchers have attempted to infer properties of the immune response from epidemiological studies, with mathematical models frequently being used to bridge the gap between immunological theory and population-level data on schistosome infection and immune responses. Here, building upon earlier model findings, stochastic individual-based models were used to identify model structures consistent with observed field patterns of Schistosoma haematobium infection and antibody responses, including their distributions in cross-sectional surveys, and the observed treatment-induced antibody switch. We found that the observed patterns of infection and antibody were most consistent with models in which a long-lived protective antibody response is stimulated by the death of adult S. haematobium worms and reduces worm fecundity. These findings are discussed with regard to current understanding of human immune responses to schistosome infection. DOI
- Origin and Fate of A/H1N1 Influenza in Scotland during 2009
The spread of influenza has usually been described by a 'density' model where the largest centres of population drive the epidemic within a country. An alternative model emphasising the role of air travel has recently been developed. We have examined the relative importance of the two in the context of the 2009 H1N1 influenza epidemic in Scotland. We obtained genome sequences of 71 strains representative of the geographic and temporal distribution of H1N1 influenza during the summer and winter phases of the pandemic in 2009. We analysed these strains, together with another 128 from the rest of the United Kingdom and 293 globally distributed strains using maximum likelihood phylogenetics and Bayesian phylogeographic methods. This revealed strikingly different epidemic patterns within Scotland in the early and late part of 2009. The summer epidemic in Scotland was characterised by multiple independent introductions from both international and other UK sources, followed by major local expansion of a single clade which probably originated in Birmingham. The winter phase in contrast, was more diverse genetically with several clades of similar size in different locations, some of which had no particularly close phylogenetic affinity to strains sampled from either Scotland or England. Overall there was evidence to support both models with significant links demonstrated between N. American sequences and those from England, and between England and East Asia, indicating major air travel routes played an important role in the pattern of spread of the pandemic both within the UK and globally. DOI
- Hematological profile of East African Short-Horn Zebu calves: From birth to 51 weeks of age
This paper is the first attempt to accurately describe the hematological parameters for any African breed of cattle, by capturing the changes in these parameters over the first 12 months of an animal’s life using a population-based sample of calves reared under field conditions and natural disease challenge. Using a longitudinal study design, a stratified clustered random sample of newborn calves was recruited into the IDEAL study and monitored at 5-weekly intervals until 51 weeks of age. The blood cell analysis performed at each visit included: packed cell volume; red cell count; red cell distribution width; mean corpuscular volume; mean corpuscular hemoglobin concentration; hemoglobin concentration; white cell count; absolute lymphocyte, eosinophil, monocyte, and neutrophil counts; platelet count; mean platelet volume; and total serum protein. The most significant age-related change in the red cell parameters was a rise in red cell count and hemoglobin concentration during the neonatal period. This is in contrast to what is reported for other ruminants, including European cattle breeds where the neonatal period is marked by a fall in the red cell parameters. There is a need to establish breed-specific reference ranges for blood parameters for indigenous cattle breeds. The possible role of the postnatal rise in the red cell parameters in the adaptability to environmental constraints and innate disease resistance warrants further research into the dynamics of blood cell parameters of these breeds. DOI
- Lysogeny with Shiga Toxin 2-Encoding Bacteriophages Represses Type III Secretion in Enterohemorrhagic Escherichia coli
Lytic or lysogenic infections by bacteriophages drive the evolution of enteric bacteria. Enterohemorrhagic Escherichia coli (EHEC) have recently emerged as a significant zoonotic infection of humans with the main serotypes carried by ruminants. Typical EHEC strains are defined by the expression of a type III secretion (T3S) system, the production of Shiga toxins (Stx) and association with specific clinical symptoms. The genes for Stx are present on lambdoid bacteriophages integrated into the E. coli genome. Phage type (PT) 21/28 is the most prevalent strain type linked with human EHEC infections in the United Kingdom and is more likely to be associated with cattle shedding high levels of the organism than PT32 strains. In this study we have demonstrated that the majority (90%) of PT 21/28 strains contain both Stx2 and Stx2c phages, irrespective of source. This is in contrast to PT 32 strains for which only a minority of strains contain both Stx2 and 2c phages (28%). PT21/28 strains had a lower median level of T3S compared to PT32 strains and so the relationship between Stx phage lysogeny and T3S was investigated. Deletion of Stx2 phages from EHEC strains increased the level of T3S whereas lysogeny decreased T3S. This regulation was confirmed in an E. coli K12 background transduced with a marked Stx2 phage followed by measurement of a T3S reporter controlled by induced levels of the LEE-encoded regulator (Ler). The presence of an integrated Stx2 phage was shown to repress Ler induction of LEE1 and this regulation involved the CII phage regulator. This repression could be relieved by ectopic expression of a cognate CI regulator. A model is proposed in which Stx2-encoding bacteriophages regulate T3S to co-ordinate epithelial cell colonisation that is promoted by Stx and secreted effector proteins. DOI
- Modelling the within-host dynamics of the foot-and-mouth disease virus in cattle
In this paper we investigate the within-host dynamics of the foot-and-mouth disease virus (FMDV) in cattle using previously published data for 8 experimentally infected cows. An 8-compartment, 14-parameter differential equation model was fitted to data collected from each cow every 24h over the course of an infection on: (i) the concentration of FMDV genomes in the blood, (ii) the concentration of infectious virus in the blood, (iii) antibody levels, and (iv) interferon levels. Model parameters were estimated using maximum-likelihood methods. The likelihood surface was sampled using Markov chain Monte Carlo methods giving credible intervals for each of the model parameters. The model was able to capture the within-host dynamics well for 6 of the infections, with both the innate (type 1 interferon) and antibody responses playing key roles in determining the height and duration of peak levels of virus. There was considerable variation between virus dynamics in individual cattle which was only partly accounted for by inferred differences in the dose of virus received. A better understanding of the within-host dynamics also provides insights into the dynamics of infectiousness and the transmission of virus to new hosts. DOI
- Pathogenic Potential to Humans of Bovine Escherichia coli O26, Scotland
Escherichia coli O26 and O157 have similar overall prevalences in cattle in Scotland, but in humans, Shiga toxin-producing E. coli O26 infections are fewer and clinically less severe than E. coli O157 infections. To investigate this discrepancy, we genotyped E. coli O26 isolates from cattle and humans in Scotland and continental Europe. The genetic background of some strains from Scotland was closely related to that of strains causing severe infections in Europe. Nonmetric multidimensional scaling found an association between hemolytic uremic syndrome (HUS) and multilocus sequence type 21 strains and confirmed the role of stx(2) in severe human disease. Although the prevalences of E. coli O26 and O157 on cattle farms in Scotland are equivalent, prevalence of more virulent strains is low, reducing human infection risk. However, new data on E. coli O26-associated HUS in humans highlight the need for surveillance of non-O157 enterohemorrhagic E. coli and for understanding stx(2) phage acquisition. DOI
- Potential for epidemic take-off from the primary outbreak farm via livestock movements
Background: We consider the potential for infection to spread in a farm population from the primary outbreak farm via livestock movements prior to disease detection. We analyse how this depends on the time of the year infection occurs, the species transmitting, the length of infectious period on the primary outbreak farm, location of the primary outbreak, and whether a livestock market becomes involved. We consider short infectious periods of 1 week, 2 weeks and 4 weeks, characteristic of acute contagious livestock diseases. The analysis is based on farms in Scotland from 1 January 2003 to 31 July 2007.
Results: The proportion of primary outbreaks from which an acute contagious disease would spread via movement of livestock is generally low, but exhibits distinct annual cyclicity with peaks in May and August. The distance that livestock are moved varies similarly: at the time of the year when the potential for spread via movements is highest, the geographical spread via movements is largest. The seasonal patterns for cattle differ from those for sheep whilst there is no obvious seasonality for pigs. When spread via movements does occur, there is a high risk of infection reaching a livestock market; infection of markets can amplify disease spread. The proportion of primary outbreaks that would spread infection via livestock movements varies significantly between geographical regions.
Conclusions: In this paper we introduce a set-up for analysis of movement data that allows for a generalized assessment of the risk associated with infection spreading from a primary outbreak farm via livestock movements, applying this to Scotland, we assess how this risk depends upon the time of the year, species transmitting, location of the farm and other factors.DOI
- Modelling Marek's Disease Virus (MDV) infection: parameter estimates for mortality rate and infectiousness
Background: Marek's disease virus (MDV) is an economically important oncogenic herpesvirus of poultry. Since the 1960s, increasingly virulent strains have caused continued poultry industry production losses worldwide. To understand the mechanisms of this virulence evolution and to evaluate the epidemiological consequences of putative control strategies, it is imperative to understand how virulence is defined and how this correlates with host mortality and infectiousness during MDV infection. We present a mathematical approach to quantify key epidemiological parameters. Host lifespan, virus latent periods and host viral shedding rates were estimated for unvaccinated and vaccinated birds, infected with one of three MDV strains. The strains had previously been pathotyped to assign virulence scores according to pathogenicity of strains in hosts.
Results: Our analyses show that strains of higher virulence have a higher viral shedding rate, and more rapidly kill hosts. Vaccination enhances host life expectancy but does not significantly reduce the shedding rate of the virus. While the primary latent period of the virus does not vary with challenge strain nor vaccine treatment of host, the time until the maximum viral shedding rate is increased with vaccination.
Conclusions: Our approach provides the tools necessary for a formal analysis of the evolution of virulence in MDV, and potentially simpler and cheaper approaches to comparing the virulence of MDV strains.DOI
- Explaining Observed Infection and Antibody Age-Profiles in Populations with Urogenital Schistosomiasis
Urogenital schistosomiasis is a tropical disease infecting more than 100 million people in sub-Saharan Africa. Individuals in endemic areas endure repeated infections with long-lived schistosome worms, and also encounter larval and egg stages of the life cycle. Protective immunity against infection develops slowly with age. Distinctive age-related patterns of infection and specific antibody responses are seen in endemic areas, including an infection 'peak shift' and a switch in the antibody types produced. Deterministic models describing changing levels of infection and antibody with age in homogeneously exposed populations were developed to identify the key mechanisms underlying the antibody switch, and to test two theories for the slow development of protective immunity: that (i) exposure to dying (long-lived) worms, or (ii) experience of a threshold level of antigen, is necessary to stimulate protective antibody. Different model structures were explored, including alternative stages of the life cycle as the main antigenic source and the principal target of protective antibody, different worm survival distributions, antigen thresholds and immune cross-regulation. Models were identified which could reproduce patterns of infection and antibody consistent with field data. Models with dying worms as the main source of protective antigen could reproduce all of these patterns, but so could some models with other continually-encountered life stages acting as the principal antigen source. An antigen threshold enhanced the ability of the model to replicate these patterns, but was not essential for it to do so. Models including either non-exponential worm survival or cross-regulation were more likely to be able to reproduce field patterns, but neither of these was absolutely required. The combination of life cycle stage stimulating, and targeted by, antibody was found to be critical in determining whether models could successfully reproduce patterns in the data, and a number of combinations were excluded as being inconsistent with field data.DOI
- Evaluation of risks of foot-and-mouth disease in Scotland to assist with decision making during the 2007 outbreak in the UK
An outbreak of foot-and-mouth disease (FMD) occurred in Surrey on August 3, 2007. A Great Britain-wide ban on livestock movements was implemented immediately. This coincided with the start of seasonal sheep movements off the hills in Scotland; the majority of these animals are sold via markets. The ban therefore posed severe economic and animal-welfare hardships if it was to last through September and beyond. The Scottish Government commissioned an analysis to assess the risk of re-opening markets given the uncertainty about whether FMD had entered Scotland. Tracing of livestock moved from within the risk zone in England between July 16 and August 3 identified contact chains to 12 Scottish premises; veterinary field inspections found a further three unrecorded movements. No signs of infection were found on these holdings. Under the conservative assumption that a single unknown Scottish holding was infected with FMD, an estimate of the time-dependent probability of Scotland being FMD free given no detection was made. Analyses indicated that if FMD was not detected by early to mid-September then it was highly probable that Scotland was FMD free. Risk maps were produced to visualise the potential spread of FMD across Scotland if it was to spread either locally or via market sales.DOI
- How to make predictions about future infectious disease risks
Formal, quantitative approaches are now widely used to make predictions about the likelihood of an infectious disease outbreak, how the disease will spread, and how to control it. Several well-established methodologies are available, including risk factor analysis, risk modelling and dynamic modelling. Even so, predictive modelling is very much the 'art of the possible', which tends to drive research effort towards some areas and away from others which may be at least as important. Building on the undoubted success of quantitative modelling of the epidemiology and control of human and animal diseases such as AIDS, influenza, foot-and-mouth disease and BSE, attention needs to be paid to developing a more holistic framework that captures the role of the underlying drivers of disease risks, from demography and behaviour to land use and climate change. At the same time, there is still considerable room for improvement in how quantitative analyses and their outputs are communicated to policy makers and other stakeholders. A starting point would be generally accepted guidelines for 'good practice' for the development and the use of predictive models.DOI
- Escherichia coli O157 infection on Scottish cattle farms: dynamics and control
In this study, we parametrize a stochastic individual-based model of the transmission dynamics of Escherichia coli O157 infection among Scottish cattle farms and use the model to predict the impacts of both targeted and non-targeted interventions. We first generate distributions of model parameter estimates using Markov chain Monte Carlo methods. Despite considerable uncertainty in parameter values, each set of parameter values within the 95th percentile range implies a fairly similar impact of interventions. Interventions that reduce the transmission coefficient and/or increase the recovery rate of infected farms (e.g. via vaccination and biosecurity) are much more effective in reducing the level of infection than reducing cattle movement rates, which improves effectiveness only when the overall control effort is small. Targeted interventions based on farm-level risk factors are more efficient than non-targeted interventions. Herd size is a major determinant of risk of infection, and our simulations confirmed that targeting interventions at farms with the largest herds is almost as effective as targeting based on overall risk. However, because of the striking characteristic that the infection force depends weakly on the number of infected farms, no interventions that are less than 100 per cent effective can eradicate E. coli O157 infection from Scottish cattle farms, implying that eliminating the disease is impractical.DOI
- Sero-Prevalence and Incidence of A/H1N1 2009 Influenza Infection in Scotland in Winter 2009-2010
Background: Sero-prevalence is a valuable indicator of prevalence and incidence of A/H1N1 2009 infection. However, raw sero-prevalence data must be corrected for background levels of cross-reactivity (i.e. imperfect test specificity) and the effects of immunisation programmes.
Methods and Findings: We obtained serum samples from a representative sample of 1563 adults resident in Scotland between late October 2009 and April 2010. Based on a microneutralisation assay, we estimate that 44% (95% confidence intervals (CIs): 40-47%) of the adult population of Scotland were sero-positive for A/H1N1 2009 influenza by 1 March 2010. Correcting for background cross-reactivity and for recorded vaccination rates by time and age group, we estimated that 34% (27-42%) were naturally infected with A/H1N1 2009 by 1 March 2010. The central estimate increases to >40% if we allow for imperfect test sensitivity. Over half of these infections are estimated to have occurred during the study period and the incidence of infection in late October 2009 was estimated at 4.3 new infections per 1000 people per day (1.2 to 7.2), falling close to zero by April 2010. The central estimate increases to over 5.0 per 1000 if we allow for imperfect test specificity. The rate of infection was higher for younger adults than older adults. Raw sero-prevalences were significantly higher in more deprived areas (likelihood ratio trend statistic = 4.92,1 df, P = 0.03) but there was no evidence of any difference in vaccination rates.
Conclusions: We estimate that almost half the adult population of Scotland were sero-positive for A/H1N1 2009 influenza by early 2010 and that the majority of these individuals (except in the oldest age classes) sero-converted as a result of natural infection with A/H1N1 2009. Public health planning should consider the possibility of higher rates of infection with A/H1N1 2009 influenza in more deprived areas.DOI
- Risk-Targeted Selection of Agricultural Holdings for Post-Epidemic Surveillance: Estimation of Efficiency Gains
Current post-epidemic sero-surveillance uses random selection of animal holdings. A better strategy may be to estimate the benefits gained by sampling each farm and use this to target selection. In this study we estimate the probability of undiscovered infection for sheep farms in Devon after the 2001 foot-and-mouth disease outbreak using the combination of a previously published model of daily infection risk and a simple model of probability of discovery of infection during the outbreak. This allows comparison of the system sensitivity (ability to detect infection in the area) of arbitrary, random sampling compared to risk-targeted selection across a full range of sampling budgets. We show that it is possible to achieve 95% system sensitivity by sampling, on average, 945 farms with random sampling and 184 farms with risk-targeted sampling. We also examine the effect of ordering samples by risk to expedite return to a disease-free status. Risk ordering the sampling process results in detection of positive farms, if present, 15.6 days sooner than with randomly ordered sampling, assuming 50 farms are tested per day.DOI
- Schistosome Infection Intensity Is Inversely Related to Auto-Reactive Antibody Levels
In animal experimental models, parasitic helminth infections can protect the host from auto-immune diseases. We conducted a population-scale human study investigating the relationship between helminth parasitism and auto-reactive antibodies and the subsequent effect of anti-helminthic treatment on this relationship. Levels of antinuclear antibodies (ANA) and plasma IL-10 were measured by enzyme linked immunosorbent assay in 613 Zimbabweans (aged 2-86 years) naturally exposed to the blood fluke Schistosoma haematobium. ANA levels were related to schistosome infection intensity and systemic IL-10 levels. All participants were offered treatment with the anti-helminthic drug praziquantel and 102 treated schoolchildren (5-16 years) were followed up 6 months post-antihelminthic treatment. ANA levels were inversely associated with current infection intensity but were independent of host age, sex and HIV status. Furthermore, after allowing for the confounding effects of schistosome infection intensity, ANA levels were inversely associated with systemic levels of IL-10. ANA levels increased significantly 6 months after anti-helminthic treatment. Our study shows that ANA levels are attenuated in helminth-infected humans and that anti-helminthic treatment of helminth-infected people can significantly increase ANA levels. The implications of these findings are relevant for understanding both the aetiology of immune disorders mediated by auto-reactive antibodies and in predicting the long-term consequences of large-scale schistosomiasis control programs.DOI
- Relationship Between Clinical Signs and Transmission of an Infectious Disease and the Implications for Control
Control of many infectious diseases relies on the detection of clinical cases and the isolation, removal, or treatment of cases and their contacts. The success of such "reactive" strategies is influenced by the fraction of transmission occurring before signs appear. We performed experimental studies of foot-and-mouth disease transmission in cattle and estimated this fraction at less than half the value expected from detecting virus in body fluids, the standard proxy measure of infectiousness. This is because the infectious period is shorter (mean 1.7 days) than currently realized, and animals are not infectious until, on average, 0.5 days after clinical signs appear. These results imply that controversial preemptive control measures may be unnecessary; instead, efforts should be directed at early detection of infection and rapid intervention.DOI
- Promoting good practice in epidemiology
- Rapid detection of pandemic influenza in the presence of seasonal influenza
Background: Key to the control of pandemic influenza are surveillance systems that raise alarms rapidly and sensitively. In addition, they must minimise false alarms during a normal influenza season. We develop a method that uses historical syndromic influenza data from the existing surveillance system 'SERVIS' (Scottish Enhanced Respiratory Virus Infection Surveillance) for influenza-like illness (ILI) in Scotland.
Methods: We develop an algorithm based on the weekly case ratio (WCR) of reported ILI cases to generate an alarm for pandemic influenza. From the seasonal influenza data from 13 Scottish health boards, we estimate the joint probability distribution of the country-level WCR and the number of health boards showing synchronous increases in reported influenza cases over the previous week. Pandemic cases are sampled with various case reporting rates from simulated pandemic influenza infections and overlaid with seasonal SERVIS data from 2001 to 2007. Using this combined time series we test our method for speed of detection, sensitivity and specificity. Also, the 2008-09 SERVIS ILI cases are used for testing detection performances of the three methods with a real pandemic data.
Results: We compare our method, based on our simulation study, to the moving-average Cumulative Sums (Mov-Avg Cusum) and ILI rate threshold methods and find it to be more sensitive and rapid. For 1% case reporting and detection specificity of 95%, our method is 100% sensitive and has median detection time (MDT) of 4 weeks while the Mov-Avg Cusum and ILI rate threshold methods are, respectively, 97% and 100% sensitive with MDT of 5 weeks. At 99% specificity, our method remains 100% sensitive with MDT of 5 weeks. Although the threshold method maintains its sensitivity of 100% with MDT of 5 weeks, sensitivity of Mov-Avg Cusum declines to 92% with increased MDT of 6 weeks. For a two-fold decrease in the case reporting rate (0.5%) and 99% specificity, the WCR and threshold methods, respectively, have MDT of 5 and 6 weeks with both having sensitivity close to 100% while the Mov-Avg Cusum method can only manage sensitivity of 77% with MDT of 6 weeks. However, the WCR and Mov-Avg Cusum methods outperform the ILI threshold method by 1 week in retrospective detection of the 2009 pandemic in Scotland.
Conclusions: While computationally and statistically simple to implement, the WCR algorithm is capable of raising alarms, rapidly and sensitively, for influenza pandemics against a background of seasonal influenza. Although the algorithm was developed using the SERVIS data, it has the capacity to be used at other geographic scales and for different disease systems where buying some early extra time is critical.DOI
- Potential for transmission of infections in networks of cattle farms
The aim of this analysis is to evaluate how generic properties of networks of livestock farms connected by movements of cattle impact on the potential for spread of infectious diseases. We focus on endemic diseases with long infectious periods in affected cattle, such as bovine tuberculosis. Livestock farm networks provide a rare example of large but fully specified directed contact networks, allowing investigations into how properties of such networks impact the potential for spread of infections within them. Here we quantify the latter in terms of the basic reproduction number, R-0, and partition the contributions to R-0 from first order moments (mean contact rates) and second order moments (variances and covariances of contact rates) of the farm contact matrices. We find that the second order properties make a substantial contribution to the magnitude of R-0, similarly to that reported for other populations. Importantly, however, we find that the magnitude of these effects depends on exactly how the contacts between farms are defined or weighted. We note that the second order properties of a directed contact network may vary through time even with little change in the mean contact rates or in overall connectedness of the network. (C) 2010 Elsevier B.V. All rights reserved.DOI
- Sheep Movement Networks and the Transmission of Infectious Diseases
Background and Methodology: Various approaches have been used to investigate how properties of farm contact networks impact on the transmission of infectious diseases. The potential for transmission of an infection through a contact network can be evaluated in terms of the basic reproduction number, R-0. The magnitude of R-0 is related to the mean contact rate of a host, in this case a farm, and is further influenced by heterogeneities in contact rates of individual hosts. The latter can be evaluated as the second order moments of the contact matrix (variances in contact rates, and co-variance between contacts to and from individual hosts). Here we calculate these quantities for the farms in a country-wide livestock network: >15,000 Scottish sheep farms in each of 4 years from July 2003 to June 2007. The analysis is relevant to endemic and chronic infections with prolonged periods of infectivity of affected animals, and uses different weightings of contacts to address disease scenarios of low, intermediate and high animal-level prevalence.
Principal Findings and Conclusions: Analysis of networks of Scottish farms via sheep movements from July 2003 to June 2007 suggests that heterogeneities in movement patterns (variances and covariances of rates of movement on and off the farms) make a substantial contribution to the potential for the transmission of infectious diseases, quantified as R-0, within the farm population. A small percentage of farms (<20%) contribute the bulk of the transmission potential (>80%) and these farms could be efficiently targeted by interventions aimed at reducing spread of diseases via animal movement.DOI
- Spread of E. coli O157 infection among Scottish cattle farms: Stochastic models and model selection
Identifying risk factors for the presence of Escherichia coli O157 infection on cattle farms is important for understanding the epidemiology of this zoonotic infection in its main reservoir and for informing the design of interventions to reduce the public health risk. Here, we use data from a large-scale field study carried out in Scotland to fit both "SIS"-type dynamical models and statistical risk factor models. By comparing the fit (assessed using maximum likelihood) of different dynamical models we are able to identify the most parsimonious model (using the AIC statistic) and compare it with the model suggested by risk factor analysis. Both approaches identify 2 key risk factors: the movement of cattle onto the farm and the number of cattle on the farm. There was no evidence for a role of other livestock species or seasonality, or of significant risk of local spread. However, the most parsimonious dynamical model does predict that farms can infect other farms through routes other than cattle movement, and that there is a nonlinear relationship between the force of infection and the number of infected farms. An important prediction from the most parsimonious model is that although only approximately 20% farms may harbour E. coli O157 infection at any given time approximately 80% may harbour infection at some point during the course of a year. DOI
- Inference for individual-level models of infectious diseases in large populations
Individual Level Models (ILMs), a new class of models, are being applied to infectious epidemic data to aid in the understanding of the spatio-temporal dynamics of infectious diseases These models are highly flexible and intuitive: and can be parameterised under a Bayesian framework via Markov chain Monte Carlo (MCMC) methods Unfortunately, this parameterisation can be difficult to implement clue to intense computational requirements when calculating the full posterior for large, or even moderately large, susceptible populations, or when missing data are present Here we detail a methodology v that can be used to estimate parameters for such large, and/or incomplete, data. sets This is clone in the context of a study of the UK 2001 foot-and-mouth disease (FMD) epidemic
- Estimating risk factors for farm-level transmission of disease: foot and mouth disease during the 2001 epidemic in Great Britain
Controlling an epidemic would be aided by establishing whether particular individuals in infected populations are more likely to transmit infection. However, few analyses have characterised such individuals. Such analyses require both data on who infected whom and on the likely determinants of transmission; data that are available at the farm level for the 2001 Foot and Mouth Disease epidemic in Great Britain. Using these data a putative number of daughter infected premises (IPs) resulting from each IP was calculated where these daughters were within 3km of the IP. A set of possible epidemiological, demographic, spatial and temporal risk factors were analysed, with the final multivariate generalised linear model (Poisson error term) having 6 statistically significant (p DOI
- Statistical modeling of holding level susceptibility to infection during the 2001 foot and mouth disease epidemic in Great Britain
Background: An understanding of the factors that determine the risk of members of a susceptible population becoming infected is essential for estimating the potential for disease spread, as opposed to just focusing on transmission from an infected population. Furthermore, analysis of the risk factors can reveal important characteristics of an epidemic and further develop understanding of the processes operating. Methods: This paper describes the development of a mixed effects logistic regression model of susceptibility of holdings to foot and mouth disease (FMD) during the 2001 epidemic in Great Britain following the imposition of a national ban on the movements of susceptible animals (NMB). Results: The principal risk factors identified in the model were shorter distances to the nearest infectious seed (a holding infected before the NMB) and the county of the holding (principally Cumbria). Additional risk factors included holdings that are mixed species rather than single species, the surface area of the holding, and the number of cattle within 10 km (all p <0.001), but not surrounding sheep densities (p > 0.1). The fit of the model was evaluated using the area under the receiver operator characteristic curve (ROC) and the Hosmer and Lemeshow Chi-squared statistic; the fit was good with both tests (area under the ROC = 0.962 and Hosmer and Lemeshow Chi-squared statistic = 49.98 (p > 0.1)). Conclusions: Holdings at greatest risk of infection can be identified using simple readily available risk factors; this information could be employed in the control of future FMD epidemics. (C) 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. DOI
- Temporal and spatial patterns of bovine Escherichia coli O157 prevalence and comparison of temporal changes in the patterns of phage types associated with bovine shedding and human E. coli O157 cases in Scotland between 1998-2000 and 200
Escherichia coli O157 is an important cause of acute diarrhoea, haemorrhagic colitis and, especially in children, haemolytic uraemic syndrome (HUS). Incidence rates for human E. coli O157 infection in Scotland are higher than most other United Kingdom, European and North American countries. Cattle are considered the main reservoir for E. coli O157. Significant associations between livestock related exposures and human infection have been identified in a number of studies.
Animal Studies: There were no statistically significant differences (P = 0.831) in the mean farm-level prevalence between the two studies (SEERAD: 0.218 (95%CI: 0.141-0.32); IPRAVE: 0.205 (95%CI: 0.135-0.296)). However, the mean pat-level prevalence decreased from 0.089 (95%CI: 0.075-0.105) to 0.040 (95%CI: 0.028-0.053) between the SEERAD and IPRAVE studies respectively (P < 0.001). Highly significant (P < 0.001) reductions in mean pat-level prevalence were also observed in the spring, in the North East and Central Scotland, and in the shedding of phage type (PT) 21/28. Human Cases: Contrasting the same time periods, there was a decline in the overall comparative annual reported incidence of human cases as well as in all the major PT groups except 'Other' PTs. For both cattle and humans, the predominant phage type between 1998 and 2004 was PT21/28 comprising over 50% of the positive cattle isolates and reported human cases respectively. The proportion of PT32, however, was represented by few (<5%) of reported human cases despite comprising over 10% of cattle isolates. Across the two studies there were differences in the proportion of PTs 21/28, 32 and 'Other' PTs in both cattle isolates and reported human cases; however, only differences in the cattle isolates were statistically significant (P = 0.002).
There was no significant decrease in the mean farm-level prevalence of E. coli O157 between 1998 and 2004 in Scotland, despite significant declines in mean pat-level prevalence. Although there were declines in the number of human cases between the two study periods, there is no statistically significant evidence that the overall rate (per 100,000 population) of human E. coli O157 infections in Scotland over the last 10 years has altered. Comparable patterns in the distribution of PTs 21/28 and 32 between cattle and humans support a hypothesized link between the bovine reservoir and human infections. This emphasizes the need to apply and improve methods to reduce bovine shedding of E. coli O157 in Scotland where rates appear higher in both cattle and human populations, than in other countries. DOI
- Effect of the initial dose of foot-and-mouth disease virus on the early viral dynamics within pigs
This paper investigates the early viral dynamics of foot-and-mouth disease (FMD) within infected pigs. Using an existing within-host model, we investigate whether individual variation can be explained by the effect of the initial dose of FMD virus. To do this, we consider the experimental data on the concentration of FMD virus genomes in the blood (viral load). In this experiment, 12 pigs were inoculated with one of three different doses of FMD virus: low; medium; or high. Measurements of the viral load were recorded over a time course of approximately 11 days for every 8 hours. The model is a set of deterministic differential equations with the following variables: viral load; virus in the interstitial space; and the proportion of epithelial cells available for infection, infected and uninfected. The model was fitted to the data for each animal individually and also simultaneously over all animals varying only the initial dose. We show that the general trend in the data can be explained by varying only the initial dose. The higher the initial dose the earlier the development of a detectable viral load.DOI
- Evaluating different PrP genotype selection strategies for expected severity of scrapie outbreaks and genetic progress in performance in commercial sheep
Stochastic computer simulations were used for quantifying the effect of selecting on prion protein (PrP) genotype on the risk of major outbreaks of classical scrapie and the rate of genetic progress in performance in commercial sheep populations already undergoing selection on performance. The risk of a major outbreak on a flock was measured by the basic reproduction ratio (R-0). The effectiveness of different PrP selection strategies for reducing the population risk was assessed by the percentage of flocks with R-0 < 1. When compared with the scenario where there was no selection on PrP genotype, selection against the VRQ allele had a minimal impact on genetic progress for performance traits. However, this strategy was not sufficient to eliminate the population risk after 15 years of selection when the initial frequency of the ARR allele was relatively low. More extreme PrP selection strategies aimed at increasing the frequency of the ARR allele and decreasing the frequency of the VRQ allele led to decreases in the rate of genetic progress for performance but reduced the population risk to very low values. The reduction in genetic progress was only large when the initial ARR frequency was low and, in general, the risk of major epidemics was very small when the frequency of this allele reached 0.7. (C) 2009 Elsevier B.V. All rights reserved.DOI
- The role of pre-emptive culling in the control of foot-and-mouth disease
The 2001 foot-and-mouth disease epidemic was controlled by culling of infectious premises and preemptive culling intended to limit the spread of disease. Of the control strategies adopted, routine culling of farms that were contiguous to infected premises caused the most controversy. Here we perform a retrospective analysis of the culling of contiguous premises as performed in 2001 and a simulation study of the effects of this policy on reducing the number of farms affected by disease. Our simulation results support previous studies and show that a national policy of contiguous premises (CPs) culling leads to fewer farms losing livestock. The optimal national policy for controlling the 2001 epidemic is found to be the targeting of all contiguous premises, whereas for localized outbreaks in high animal density regions, more extensive fixed radius ring culling is optimal. Analysis of the 2001 data suggests that the lowest-risk CPs were generally prioritized for culling, however, even in this case, the policy is predicted to be effective. A sensitivity analysis and the development of a spatially heterogeneous policy show that the optimal culling level depends upon the basic reproductive ratio of the infection and the width of the dispersal kernel. These analyses highlight an important and probably quite general result: optimal control is highly dependent upon the distance over which the pathogen can be transmitted, the transmission rate of infection and local demography where the disease is introduced.DOI
- Detection of mortality clusters associated with highly pathogenic avian influenza in poultry: a theoretical analysis
Rapid detection of infectious disease outbreaks is often crucial for their effective control. One example is highly pathogenic avian influenza (HPAI) such as H5N1 in commercial poultry flocks. There are no quantitative data, however, on how quickly the effects of HPAI infection in poultry flocks can be detected. Here, we study, using an individual-based mathematical model, time to detection in chicken flocks. Detection is triggered when mortality, food or water intake or egg production in layers pass recommended thresholds suggested from the experience of past HPAI outbreaks. We suggest a new threshold for caged flocks-the cage mortality detection threshold-as a more sensitive threshold than current ones. Time to detection is shown to depend nonlinearly on R-0 and is particularly sensitive for R-0 < 10. It also depends logarithmically on flock size and number of birds per cage. We also examine how many false alarms occur in uninfected flocks when we vary detection thresholds owing to background mortality. The false alarm rate is shown to be sensitive to detection thresholds, dependent on flock size and background mortality and independent of the length of the production cycle. We suggest that current detection thresholds appear sufficient to rapidly detect the effects of a high R-0 HPAI strain such as H7N7 over a wide range of flock sizes. Time to detection of the effects of a low R-0 HPAI strain such as H5N1 can be significantly improved, particularly for large flocks, by lowering detection thresholds, and this can be accomplished without causing excessive false alarms in uninfected flocks. The results are discussed in terms of optimizing the design of disease surveillance programmes in general.DOI
- Super-shedding and the link between human infection and livestock carriage of Escherichia coli O157
Cattle that excrete more Escherichia coli O157 than others are known as super-shedders. Super-shedding has important consequences for the epidemiology of E. coli O157 in cattle — its main reservoir — and for the risk of human infection, particularly owing to environmental exposure. Ultimately, control measures targeted at super-shedders may prove to be highly effective. We currently have only a limited understanding of both the nature and the determinants of super-shedding. However, super-shedding has been observed to be associated with colonization at the terminal rectum and might also occur more often with certain pathogen phage types. More generally, epidemiological evidence suggests that super-shedding might be important in other bacterial and viral infections. DOI
- Geographic and topographic determinants of local FMD transmission applied to the 2001 UK FMD epidemic
Background: Models of Foot and Mouth Disease (FMD) transmission have assumed a homogeneous landscape across which Euclidean distance is a suitable measure of the spatial dependency of transmission. This paper investigated features of the landscape and their impact on transmission during the period of predominantly local spread which followed the implementation of the national movement ban during the 2001 UK FMD epidemic. In this study 113 farms diagnosed with FMD which had a known source of infection within 3 km (cases) were matched to 188 control farms which were either uninfected or infected at a later timepoint. Cases were matched to controls by Euclidean distance to the source of infection and farm size. Intervening geographical features and connectivity between the source of infection and case and controls were compared.
- Temporal trends in the discovery of human viruses
On average, more than two new species of human virus are reported every year. We constructed the cumulative species discovery curve for human viruses going back to 1901. We fitted a statistical model to these data; the shape of the curve strongly suggests that the process of virus discovery is far from complete. We generated a 95% credible interval for the pool of as yet undiscovered virus species of 38-562. We extrapolated the curve and generated an estimate of 10-40 new species to be discovered by 2020. Although we cannot predict the level of health threat that these new viruses will present, we conclude that novel virus species must be anticipated in public health planning. More systematic virus discovery programmes, covering both humans and potential animal reservoirs of human viruses, should be considered.DOI
- Accuracy of models for the 2001 foot-and-mouth epidemic
Since 2001 models of the spread of foot-and-mouth disease, supported by the data from the UK epidemic, have been expounded as some of the best examples of problem-driven epidemic models. These claims are generally based on a comparison between model results and epidemic data at fairly coarse spatio-temporal resolution. Here, we focus on a comparison between model and data at the individual farm level, assessing the potential of the model to predict the infectious status of farms in both the short and long terms. Although the accuracy with which the model predicts farms reporting infection is between 5 and 15%, these low levels are attributable to the expected level of variation between epidemics, and are comparable to the agreement between two independent model simulations. By contrast, while the accuracy of predicting culls is higher (20-30%), this is lower than expected from the comparison between model epidemics. These results generally support the contention that the type of the model used in 2001 was a reliable representation of the epidemic process, but highlight the difficulties of predicting the complex human response, in terms of control strategies to the perceived epidemic risk.DOI
- Estimating the burden of rhodesiense sleeping sickness during an outbreak in Serere, eastern Uganda
Background: Zoonotic sleeping sickness, or HAT (Human African Trypanosomiasis), caused by infection with Trypanosoma brucei rhodesiense, is an under-reported and neglected tropical disease. Previous assessments of the disease burden expressed as Disability-Adjusted Life Years (DALYs) for this infection have not distinguished T.b. rhodesiense from infection with the related, but clinically distinct Trypanosoma brucei gambiense form. T.b. rhodesiense occurs focally, and it is important to assess the burden at the scale at which resource-allocation decisions are made.
Methods: The burden of T.b. rhodesiense was estimated during an outbreak of HAT in Serere, Uganda. We identified the unique characteristics affecting the burden of rhodesiense HAT such as age, severity, level of under-reporting and duration of hospitalisation, and use field data and empirical estimates of these to model the burden imposed by this and other important diseases in this study population. While we modelled DALYs using standard methods, we also modelled uncertainty of our parameter estimates through a simulation approach. We distinguish between early and late stage HAT morbidity, and used disability weightings appropriate for the T.b. rhodesiense form of HAT. We also use a model of under-reporting of HAT to estimate the contribution of unreported mortality to the overall disease burden in this community, and estimate the cost-effectiveness of hospital-based HAT control.
Results: Under-reporting accounts for 93% of the DALY estimate of rhodesiense HAT. The ratio of reported malaria cases to reported HAT cases in the same health unit was 133: 1, however, the ratio of DALYs was 3:1. The age productive function curve had a close correspondence with the HAT case distribution, and HAT cases occupied more patient admission time in Serere during 1999 than all other infectious diseases other than malaria. The DALY estimate for HAT in Serere shows that the burden is much greater than might be expected from its relative incidence. Hospital based control in this setting appears to be highly cost-effective, highlighting the value of increasing coverage of therapy and reducing under-reporting.
Conclusion: We show the utility of calculating DALYs for neglected diseases at the local decision making level, and emphasise the importance of improved reporting systems for acquiring a better understanding of the burden of neglected zoonotic diseases.DOI
- Reconstructing historical changes in the force of infection of dengue fever in Singapore: implications for surveillance and control
Objective To reconstruct the historical changes in force of dengue infection in Singapore, and to better understand the relationship between control of Aedes mosquitoes and incidence of classic dengue fever.
Methods Seroprevalence data were abstracted from surveys performed in Singapore from 1982 to 2002. These data were used to develop two mathematical models of age seroprevalence. In the first model, force of infection was allowed to vary independently each year, while in the second it was described by a polynomial function. Model-predicted temporal trends were analysed using linear regression. Time series techniques were employed to investigate periodicity in predicted forces of infection, dengue fever incidence and mosquito breeding.
Findings Force of infection estimates showed a significant downward trend from 1966, when vector control was instigated. Force of infection estimates from both models reproduced significant increases in the percentage and average age of the population susceptible to dengue infections. Importantly, the year-on-year model independently predicted a five to six year periodicity that was also displayed by clinical incidence but absent from the Aedes household index.
Conclusion We propose that the rise in disease incidence was due in part to a vector-control-driven reduction in herd immunity in older age groups that are more susceptible to developing clinical dengue.DOI
- Epidemiology - Emerging diseases go global
- Risk factors for the presence of high-level shedders of Escherichia coli O157 on Scottish farms
Escherichia coli O157 infections are the cause of sporadic or epidemic cases of often bloody diarrhea that can progress to hemolytic uremic syndrome (HUS), a systematic microvascular syndrome with predominately renal and neurological complications. HUS is responsible for most deaths associated with E. coli O157 infection. From March 2002 to February 2004, approximately 13,000 fecal pat samples from 481 farms with finishing/store cattle throughout Scotland were examined for the presence of E. coli O157. A total of 441 fecal pats from 91 farms tested positive for E. coli O157. From the positive samples, a point estimate for high-level shedders was identified using mixture distribution analysis on counts of E. coli O157. Models were developed based on the confidence interval surrounding this point estimate (high-level shedder, greater than 10(3) or greater than 104 CFU g(-1) feces). The mean prevalence on high-level-shedding farms was higher than that on low-level-shedding farms. The presence of a high-level shedder on a farm was found to be associated with a high proportion of low-level shedding, consistent with the possibility of a higher level of transmission. Analysis of risk factors associated with the presence of a high-level shedder on a farm suggested the importance of the pathogen and individual host rather than the farm environment. The proportion of high-level shedders of phage 21/28 was higher than expected by chance. Management-related risk factors that were identified included the type of cattle (female breeding cattle) and cattle stress (movement and weaning), as opposed to environmental factors, such as water supply and feed.DOI
- Quantification of Peyer's patches in Cheviot sheep for future scrapie pathogenesis studies
Peyer's patches (PPs) are the most probable sites of intestinal uptake of the transmissible spongiform encephalopathy (TSE) agent. The amount of PP tissue varies considerably between different age groups of individuals, and whether this variation is related to susceptibility to TSE infection raises an intriguing possibility. The purpose of this study was to determine the surface area of PP tissue and the number of associated lymphoid follicles in different age groups of Neuropathogenesis Unit (NPU) Cheviot sheep. Terminal ilea were obtained from 33 sheep of different ages. Samples of ileal tissue were collected for immunocytochemistry and immunolabelled for prion protein (PrP). Specimens were then fixed in acetic acid, stained with methylene blue and transilluminated. Image analysis software was used to calculate the area of intestinal and PP tissue. The number of associated lymphoid follicles was determined using a dissecting microscope. Results showed a marked fall in surface area of PP tissue and lymphoid follicle density around puberty (about 8-9 months of age in NPU Cheviot sheep) and both measures remained low throughout adulthood. Using the Spearman's rank correlation coefficient, r(s), these two measures were found to be closely correlated (r(s)= 0.899, n = 33, P < 0.0001). There was also a significant (negative) correlation between age and the two respective measures (surface area of PP tissue versus age, r(s), = -0.879 (n = 33, P < 0.0001); lymphoid follicle density versus age r(s) = -0.943 (n = 33, P < 0.0001). Immunolabelling for PrP was observed primarily in the light zone of lymphoid follicles. Results obtained from this study are useful for future oral pathogenesis studies of the NPU Cheviot flock. They may also offer a possible biological explanation for the apparent age-susceptibility relationship observed in natural cases of TSEs and might help to explain the young age-distribution of cases. (c) 2007 Elsevier B.V. All rights reserved.DOI
- Ecological origins of novel human pathogens
A systematic literature survey suggests that there are 1399 species of human pathogen. Of these, 87 were first reported in humans in the years since 1980. The new species are disproportionately viruses, have a global distribution, and are mostly associated with animal reservoirs. Their emergence is often driven by ecological changes, especially with how human populations interact with animal reservoirs. Here, we review the process of pathogen emergence over both ecological and evolutionary time scales by reference to the "pathogen pyramid." We also consider the public health implications of the continuing emergence of new pathogens, focusing on the importance of international surveillance. DOI
- Effect of data quality on estimates of farm infectiousness trends in the UK 2001 foot-and-mouth disease epidemic
Most of the mathematical models that were developed to study the UK 2001 foot-and-mouth disease epidemic assumed that the infectiousness of infected premises was constant over their infectious periods. However, there is some controversy over whether this assumption is appropriate. Uncertainty about which farm infected which in 2001 means that the only method to determine if there were trends in farm infectiousness is the fitting of mechanistic mathematical models to the epidemic data. The parameter values that are estimated using this technique, however, may be influenced by missing and inaccurate data. In particular to the UK 2001 epidemic, this includes unreported infectives, inaccurate farm infection dates and unknown farm latent periods. Here, we show that such data degradation prevents successful determination of trends in farm infectiousness. DOI
- Modelling the epidemiology and transmission of Verocytotoxin-producing Escherichia coli serogroups O26 and O103 in two different calf cohorts
Mathematical models are constructed to investigate the population dynamics of Verocytotoxin-producing Escherichia coli (VTEC) serogroups O26 and O103 in two different calf cohorts. We compare the epidemiological characteristics of these two serogroups within the same calf cohort as well as the same serogroups between the two calf cohorts. The sources of infection are quantified for both calf cohort studies. VTEC serogroups O26 and O103 mainly differ in the rate at which calves acquire infection from sources other than infected calves, while infected calves typically remain infectious for less than 1 week regardless of the serogroups. Fewer than 20% of VTEC-positive samples are the result of calf-to-calf transmission. PFGE typing data are available for VTEC-positive samples to further subdivide the serogroup data in one of the two calf cohort studies. For serogroup O26 but not O103, there is evidence for unequal environmental exposure to infection with different PFGE types. DOI
- Metapopulation dynamics of Escherichia coli O157 in cattle: an exploratory model
Livestock movement is thought to be a risk factor for the transmission of infectious diseases of farm animals. Simple mathematical models were constructed for the transmission of Escherichia coli serogroup O157 between Scottish cattle farms, and the models were used in a preliminary exploration of factors contributing to the levels of infection reported in the field. The results suggest that cattle movement can make a significant contribution to the observed prevalence of E. coli O157-positive farms, but is not by itself sufficient for the persistence of E. coli O157. The results also suggest that cattle movements involving infected farms with cattle shedding an exceptional amount of E. coli O157, 'super-shedders', also make a substantial contribution to the prevalence of infected farms. Simulations indicate that E. coli O157 could have reached the currently observed prevalence levels in less than a decade. Implications and findings from our models are discussed in relation to possible control of E. coli O157 in Scottish cattle. DOI
- Herd-level risk factors associated with the presence of Phage type 21/28 E-coli O157 on Scottish cattle farms
Background: E. coli O157 is a bacterial pathogen that is shed by cattle and can cause severe disease in humans. Phage type (PT) 21/28 is a subtype of E. coli O157 that is found across Scotland and is associated with particularly severe human morbidity.
Methods: A cross-sectional survey of Scottish cattle farms was conducted in the period Feb 2002-Feb 2004 to determine the prevalence of E. coli O157 in cattle herds. Data from 88 farms on which E. coli O157 was present were analysed using generalised linear mixed models to identify risk factors for the presence of PT 21/28 specifically.
Results: The analysis identified private water supply, and northerly farm location as risk factors for PT 21/28 presence. There was a significant association between the presence of PT 21/28 and an increased number of E. coli O157 positive pat samples from a farm, and PT 21/28 was significantly associated with larger E. coli O157 counts than non-PT 21/28 E. coli O157.
Conclusion: PT 21/28 has significant risk factors that distinguish it from other phage types of E. coli O157. This finding has implications for the control of E. coli O157 as a whole and suggests that control could be tailored to target the locally dominant PT.DOI
- Prevalence and virulence factors of Escherichia coli serogroups O26, O103, O111, and O145 shed by cattle in Scotland
A national survey was conducted to determine the prevalence of Escherichia coli O26, O103, O111, and O145 in feces of Scottish cattle. In total, 6,086 fecal pats from 338 farms were tested. The weighted mean percentages of farms on which shedding was detected were 23% for E. coli O26, 22% for E. coli O103, and 10% for E. coli O145. The weighted mean prevalences in fecal pats were 4.6% for E. coli O26, 2.7% for E. coli O103, and 0.7% for E. coli 0145. No E. coli 0111 was detected. Farms with cattle shedding E. coli serogroup O26, O103, or O145 were widely dispersed across Scotland and were identified most often in summer and autumn. However, on individual farms, fecal shedding of E. coli O26, O103, or 0145 was frequently undetectable or the numbers of pats testing positive were small. For serogroup O26 or O103 there was clustering of positive pats within management groups, and the presence of an animal shedding one of these serogroups was a positive predictor for shedding by others, suggesting local transmission of infection. Carriage of vtx was rare in E. coli O103 and O145 isolates, but 49.0% of E. coli O26 isolates possessed vtx(1) invariably vtx(1) alone or vtx(1) and vtx(2) together. The carriage of eae and ehxA genes was highly associated in all three serogroups. Among E. coli serogroup O26 isolates, 28.9% carried vtx, eae, and ehxA-a profile consistent with E. coli O26 strains known to cause human disease.DOI
- Comparative evidence for a link between Peyer's patch development and susceptibility to transmissible spongiform encephalopathies
Epidemiological analyses indicate that the age distribution of natural cases of transmissible spongiform encephalopathies (TSEs) reflect age-related risk of infection, however, the underlying mechanisms remain poorly understood. Using a comparative approach, we tested the hypothesis that, there is a significant correlation between risk of infection for scrapie, bovine spongiform encephalopathy (BSE) and variant CJD (vCJD), and the development of lymphoid tissue in the gut. DOI
- Heterogeneous shedding of Escherichia coli O157 in cattle and its implications for control
Identification of the relative importance of within- and between-host variability in infectiousness and the impact of these heterogeneities on the transmission dynamics of infectious agents can enable efficient targeting of control measures. Cattle, a major reservoir host for the zoonotic pathogen Escherichia coli O157, are known to exhibit a high degree of heterogeneity in bacterial shedding densities. By relating bacterial count to infectiousness and fitting dynamic epidemiological models to prevalence data from a cross-sectional survey of cattle farms in Scotland, we identify a robust pattern: approximately 80% of the transmission arises from the 20% most infectious individuals. We examine potential control options under a range of assumptions about within- and between-host variability in infection dynamics. Our results show that the within-herd basic reproduction ratio, R(0), could be reduced to DOI
- Topographic determinants of foot and mouth disease transmission in the UK 2001 epidemic
A key challenge for modelling infectious disease dynamics is to understand the spatial spread of infection in real landscapes. This ideally requires a parallel record of spatial epidemic spread and a detailed map of susceptible host density along with relevant transport links and geographical features. DOI
- Optimal reactive vaccination strategies for a foot-and-mouth outbreak in the UK
Foot-and-mouth disease (FMD) in the UK provides an ideal opportunity to explore optimal control measures for an infectious disease. The presence of fine-scale spatio-temporal data for the 2001 epidemic has allowed the development of epidemiological models that are more accurate than those generally created for other epidemics and provide the opportunity to explore a variety of alternative control measures. Vaccination was not used during the 2001 epidemic; however, the recent DEFRA (Department for Environment Food and Rural Affairs) contingency plan details how reactive vaccination would be considered in future. Here, using the data from the 2001 epidemic, we consider the optimal deployment of limited vaccination capacity in a complex heterogeneous environment. We use a model of FMD spread to investigate the optimal deployment of reactive ring vaccination of cattle constrained by logistical resources. The predicted optimal ring size is highly dependent upon logistical constraints but is more robust to epidemiological parameters. Other ways of targeting reactive vaccination can significantly reduce the epidemic size; in particular, ignoring the order in which infections are reported and vaccinating those farms closest to any previously reported case can substantially reduce the epidemic. This strategy has the advantage that it rapidly targets new foci of infection and that determining an optimal ring size is unnecessary. DOI
- Enhancement of bacterial competitive fitness by apramycin resistance plasmids from non-pathogenic Escherichia coli
The study of antibiotic resistance has in the past focused on organisms that are pathogenic to humans or animals. However, the development of resistance in commensal organisms is of concern because of possible transfer of resistance genes to zoonotic pathogens. Conjugative plasmids are genetic elements capable of such transfer and are traditionally thought to engender a fitness burden on host bacteria. In this study, conjugative apramycin resistance plasmids isolated from newborn calves were characterized. Calves were raised on a farm that had not used apramycin or related aminoglycoside antibiotics for at least 20 months prior to sampling. Of three apramycin resistance plasmids, one was capable of transfer at very high rates and two were found to confer fitness advantages on new Escherichia coli hosts. This is the first identification of natural plasmids isolated from commensal organisms that are able to confer a fitness advantage on a new host. This work indicates that reservoirs of antibiotic resistance genes in commensal organisms might not decrease if antibiotic usage is halted. DOI
- Epidemiological implications of the contact network structure for cattle farms and the 20-80 rule
The network of movements of cattle between farm holdings is an important determinant of the potential rates and patterns of spread of infectious diseases. Because cattle movements are uni-directional, the network is unusual in that the risks of acquiring infection (by importing cattle) and of passing infection on (by exporting cattle) can be clearly distinguished, and there turns out to be no statistically significant correlation between the two. This means that the high observed degree of heterogeneity in numbers of contacts does not result in an increase in the basic reproduction number, R0, in contrast to findings from studies of other contact networks. Despite this, it is still the case that just 20% of holdings contribute at least 80% of the value of R0. DOI
- Emerging pathogens: the epidemiology and evolution of species jumps
Novel pathogens continue to emerge in human, domestic animal, wildlife and plant populations, yet the population dynamics of this kind of biological invasion remain poorly understood. Here, we consider the epidemiological and evolutionary processes underlying the initial introduction and subsequent spread of a pathogen in a new host population, with special reference to pathogens that originate by jumping from one host species to another. We conclude that, although pathogen emergence is inherently unpredictable, emerging pathogens tend to share some common traits, and that directly transmitted RNA viruses might be the pathogens that are most likely to jump between host species. DOI
- Host Range and Emerging and Reemerging Pathogens
- Modelling the epidemiology of Verocytotoxin-producing Escherichia coli serogroups in young calves
We investigate the epidemiology of 12 Verocytotoxin-producing Escherichia coli (VTEC) serogroups observed in a calf cohort on a Scottish beef farm. Fitting mathematical models to the observed time-course of infections reveals that there is significant calf-to-calf transmission of VTEC. Our models suggest that 40% of all detected infections are from calf-to-calf transmission and 60% from other sources. Variation in the rates at which infected animals recover from infection by different VTEC serogroups appears to be important. Two thirds of the observed VTEC serogroups are lost from infected calves within 1 day of infection, while the rest persist for more than 3 days. Our study has demonstrated that VTEC are transmissible between calves and are typically lost from infected animals in less than 1 week. We suggest that future field studies may wish to adopt a tighter sampling frame in order to detect all circulating VTEC serogroups in similar animal populations. DOI
- Spatial and temporal epidemiology of sporadic human cases of Escherichia coli O157 in Scotland, 1996-1999
In Scotland, between 1995 and 2000 there were between 4 and 10 cases of illness per 100000 population per year identified as being caused by Escherichia coli O157, whereas in England and Wales there were between 1 and 2 cases per 100000 population per year. Within Scotland there is significant regional variation. A cluster of high rate areas was identified in the Northeast of Scotland and a cluster of low rate areas in central-west Scotland. Temporal trends follow a seasonal pattern whilst spatial effects appeared to be distant rather than local. The best-fit model identified a significant spatial trend with case rate increasing from West to East, and from South to North. No statistically significant spatial interaction term was found. In the models fitted, the cattle population density, the human population density, and the number of cattle per person were variously significant. The findings suggest that rural/urban exposures are important in sporadic infections. DOI
- Age-related decline in carriage of ampicillin-resistant Escherichia coli in young calves
The presence of ampicillin-resistant Escherichia coli (Amp(r) E. coli) in the fecal flora of calves was monitored on a monthly basis in seven cohorts of calves. Calves were rapidly colonized by Amp(r) E. coli, with peak prevalence in cohort calves observed in the 4 months after the calves were born. The prevalence of calves yielding Amp(r) E. coli in cohorts consistently declined to low levels with increasing age of the calves (P <0.001). DOI
- Acquisition and epidemiology of antibiotic-resistant Escherichia coli in a cohort of newborn calves
The acquisition of antibiotic-resistant commensal Escherichia coli was examined in a cohort of newborn calves. DOI
- Shedding patterns of verocytotoxin-producing Escherichia coli strains in a cohort of calves and their dams on a Scottish beef farm
Rectal fecal samples were taken once a week from 49 calves on the same farm. In addition, the dams of the calves were sampled at the time of calf birth and at the end of the study. Strains of verocytotoxin-producing Escherichia coli (VTEC) were isolated from these samples by using PCR and DNA probe hybridization tests and were characterized with respect to serotype, verocytotoxin gene (vtx) type, and the presence of the intimin (eae) and hemolysin (ehxA) genes. A total of 170 VTEC strains were isolated during 21 weeks from 130 (20%) of 664 samples from calves and from 40 (47%) of 86 samples from their dams. The characteristics of the calf strains differed from those strains isolated from the dams with respect to verocytotoxin 2 and the presence of the eae gene. In addition, no calf shed the same VTEC serogroup (excluding O?) as its dam at birth or at the end of the study. The most frequently detected serogroups in calves were serogroup O26 and provisional serogroup E40874 (VTEC O26 was found in 25 calves), whereas in dams serogroup O91 and provisional serogroup E54071 were the most common serogroups. VTEC O26 shedding appeared to be associated with very young calves and declined as the calves aged, whereas VTEC O2 shedding was associated with housing of the animals. VTEC O26 strains from calves were characterized by the presence of the vtx1, eae, and ehxA genes, whereas vtx2 was associated with VTEC O2 and provisional serogroup E40874. The high prevalence of VTEC O26 and of VTEC strains harboring the eae gene in this calf cohort is notable because of the association of the O26 serogroup and the presence of the eae gene with human disease. No association between calf diarrhea and any of the VTEC serogroups was identified. DOI
- Neighbourhood control policies and the spread of infectious diseases
We present a model of a control programme for a disease outbreak in a population of livestock holdings. Control is achieved by culling infectious holdings when they are discovered and by the pre-emptive culling of livestock on holdings deemed to be at enhanced risk of infection. Because the pre-emptive control programme cannot directly identify exposed holdings, its implementation will result in the removal of both infected and uninfected holdings. This leads to a fundamental trade-off: increased levels of control produce a greater reduction in transmission by removing more exposed holdings, but increase the number of uninfected holdings culled. We derive an expression for the total number of holdings culled during the course of an outbreak and demonstrate that there is an optimal control policy, which minimizes this loss. Using a metapopulation model to incorporate local clustering of infection, we examine a neighbourhood control programme in a locally spreading outbreak. We find that there is an optimal level of control, which increases with increasing basic reproduction ratio, R(0); moreover, implementation of control may be optimal even when R(0) <1. The total loss to the population is relatively insensitive to the level of control as it increases beyond the optimal level, suggesting that over-control is a safer policy than under-control. DOI
- The construction and analysis of epidemic trees with reference to the 2001 UK foot-and-mouth outbreak
The case-reproduction ratio for the spread of an infectious disease is a critically important concept for understanding dynamics of epidemics and for evaluating impact of control measures on spread of infection. Reliable estimation of this ratio is a problem central to epidemiology and is most often accomplished by fitting dynamic models to data and estimating combinations of parameters that equate to the case-reproduction ratio. Here, we develop a novel parameter-free method that permits direct estimation of the history of transmission events recoverable from detailed observation of a particular epidemic. From these reconstructed 'epidemic trees', case-reproduction ratios can be estimated directly. We develop a bootstrap algorithm that generates percentile intervals for these estimates that shows the procedure to be both precise and robust to possible uncertainties in the historical reconstruction. Identifying and 'pruning' branches from these trees whose occurrence might have been prevented by implementation of more stringent control measures permits estimation of the possible efficacy of these alternative measures. Examination of the cladistic structure of these trees as a function of the distance of each case from its infection source reveals useful insights about the relationship between long-distance transmission events and epidemic size. We demonstrate the utility of these methods by applying them to data from the 2001 foot-and-mouth disease outbreak in the UK. DOI
- Population biology of emerging and re-emerging pathogens
Emerging and re-emerging pathogens present a huge challenge to human and veterinary medicine. Emergence is most commonly associated with ecological change, and specific risk factors are related to the type of pathogen, route of transmission and host range. The biological determinants of host range remain poorly understood but most pathogens can infect multiple hosts, and three-quarters of emerging human pathogens are zoonotic. Surveillance is a key defence against emerging pathogens but will often need to be integrated across human, domestic animal and wildlife populations.
- The origins of a new Trypanosoma brucei rhodesiense sleeping sickness outbreak in eastern Uganda
Sleeping sickness, caused by two trypanosome subspecies, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, is a parasitic disease transmitted by the tsetse fly in sub-Saharan Africa. We report on a recent outbreak of T b rhodesiense sleeping sickness outside the established south-east Ugandan focus, in Soroti District where the disease had previously been absent. Soroti District has been the subject of large-scale livestock restocking activities and, because domestic cattle are important reservoirs of T b rhodesiense, we investigated the role of cattle in the origins of the outbreak. DOI
- Population biology of multihost pathogens
The majority of pathogens, including many of medical and veterinary importance, can infect more than one species of host. Population biology has yet to explain why perceived evolutionary advantages of pathogen specialization are, in practice, outweighed by those of generalization. Factors that predispose pathogens to generalism include high levels of genetic diversity and abundant opportunities for cross-species transmission, and the taxonomic distributions of generalists and specialists appear to reflect these factors. Generalism also has consequences for the evolution of virulence and for pathogen epidemiology, making both much less predictable. The evolutionary advantages and disadvantages of generalism are so finely balanced that even closely related pathogens can have very different host range sizes.
- Epidemiology. Foot-and-mouth disease under control in the UK
- Dynamics of the 2001 UK foot and mouth epidemic: stochastic dispersal in a heterogeneous landscape
Foot-and-mouth is one of the world's most economically important livestock diseases. We developed an individual farm-based stochastic model of the current UK epidemic. The fine grain of the epidemiological data reveals the infection dynamics at an unusually high spatiotemporal resolution. We show that the spatial distribution, size, and species composition of farms all influence the observed pattern and regional variability of outbreaks. The other key dynamical component is long-tailed stochastic dispersal of infection, combining frequent local movements with occasional long jumps. We assess the history and possible duration of the epidemic, the performance of control strategies, and general implications for disease dynamics in space and time. DOI
- What is antibiotic resistance and how can we measure it?
Antibiotic resistance is being found with increasing frequency in both pathogenic and commensal bacteria of humans and animals. Quantifying resistance within and between bacterial and host populations presents scientists with complex challenges in terms of laboratory methodologies and sampling design. Here, we discuss, from an epidemiological perspective, how antibiotic resistance can be defined and measured and the limitations of current approaches.DOI
- Epidemiology and control of scrapie within a sheep flock
Mathematical models of the transmission dynamics of scrapie are used to explore the expected course of an outbreak in a sheep flock, and the potential impacts of different control measures. All models incorporate sheep demography, a long and variable scrapie incubation period, horizontal and vertical routes of transmission and genetic variation in susceptibility. Outputs are compared for models which do and do not incorporate an environmental reservoir of infectivity, and which do and do not incorporate carrier genotypes. Numerical analyses using parameter values consistent with available data indicate that, in a closed flock, scrapie outbreaks may have a duration of several decades, reduce the frequency of susceptible genotypes, and may become endemic if carrier genotypes are present. In an open flock, endemic scrapie is possible even in the absence of carriers. Control measures currently or likely to become available may reduce the incidence of cases but may be fully effective only over a period of several years.DOI
- Chemotherapy accelerates the development of acquired immune responses to Schistosoma haematobium infection
Treatment of 41 Schistosoma haematobium-infected children, 5-16 years old, with the drug praziquantel induced a switch from a predominantly IgA- specific antibody response to a predominantly IgG1 response within 12 weeks. A cross-sectional survey suggests that the same switch occurs naturally, but over several years, as children age (n = 251). The switch may be driven by alterations in cytokine levels in response to the release of antigens by dead or damaged parasites. Adults are more resistant to schistosome infection than children, and the switch to an 'adult' response suggests that praziquantel treatment may have an immunizing effect, with benefits extending beyond a transient reduction in levels of infection.
- Foot and Mouth disease infectiousness dynamics of cattle herds
- A guide to good practice for quantitative veterinary epidemiology
- Macroparasite group report: Problems in modeling the dynamics of macroparasitic systems