Louise Matthews

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.

Super-shedding cattle and the transmission dynamics of Escherichia coli O157

The prevalence of Escherichia coli O157 displays striking variability across the Scottish cattle population. On 78% of farms, in a cross-sectional survey of 952, no shedding of E. coli O157 was detected, but on a small proportion, approximately 2%, very high prevalences of infection were found (with 90-100% of pats sampled being positive). We ask whether this variation arises from the inherent stochasticity in transmission dynamics or whether it is a signature of underlying heterogeneities in the cattle population. A novel approach is taken whereby the cross-sectional data are viewed as providing independent snapshots of a dynamic process. Using maximum-likelihood methods to fit time-dependent epidemiological models to the data we obtain estimates for the rates of immigration and transmission of E. coli O157 infection - parameters which have not been previously quantified in the literature. A comparison of alternative model fits reveals that the variation in the prevalence data is best explained when a proportion of the cattle are assumed to transmit infection at much higher levels than the rest - the so-called super-shedders. Analysis of a second dataset, comprising samples taken from 32 farms at monthly intervals over a period of 1 year, additionally yields an estimate for the rate of recovery from infection. The pattern of prevalence displayed in the second dataset also strongly supports the super-shedder hypothesis.

Risk Factors for the Presence of High-Level Shedders of Escherichia coli O157 on Scottish Farms

ABSTRACT 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 103 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.

Low-coverage vaccination strategies for the conservation of endangered species

The conventional objective of vaccination programmes is to eliminate infection by reducing the reproduction number of an infectious agent to less than one, which generally requires vaccination of the majority of individuals. In populations of endangered wildlife, the intervention required to deliver such coverage can be undesirable and impractical; however, endangered populations are increasingly threatened by outbreaks of infectious disease for which effective vaccines exist. As an alternative, wildlife epidemiologists could adopt a vaccination strategy that protects a population from the consequences of only the largest outbreaks of disease. Here we provide a successful example of this strategy in the Ethiopian wolf, the worlds rarest canid, which persists in small subpopulations threatened by repeated outbreaks of rabies introduced by domestic dogs. On the basis of data from past outbreaks, we propose an approach that controls the spread of disease through habitat corridors between subpopulations and that requires only low vaccination coverage. This approach reduces the extent of rabies outbreaks and should significantly enhance the long-term persistence of the population. Our study shows that vaccination used to enhance metapopulation persistence through elimination of the largest outbreaks of disease requires lower coverage than the conventional objective of reducing the reproduction number of an infectious agent to less than one.

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.

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.

New approaches to quantifying the spread of infection

Recent major disease outbreaks, such as severe acute respiratory syndrome and foot-and-mouth disease in the UK, coupled with fears of emergence of human-to-human transmissible variants of avian influenza, have highlighted the importance of accurate quantification of disease threat when relatively few cases have occurred. Traditional approaches to mathematical modelling of infectious diseases deal most effectively with large outbreaks in large populations. The desire to elucidate the highly variable dynamics of disease spread amongst small numbers of individuals has fuelled the development of models that depend more directly on surveillance and contact-tracing data. This signals a move towards a closer interplay between epidemiological modelling, surveillance and disease-management strategies.

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.

Epidemiology: Foot-and-mouth disease under control in the UK

Following the first reported case on 20 February this year, foot-and-mouth disease spread to over 1,500 livestock farms in the United Kingdom by the end of April. From late March, the Ministry of Agriculture, Fisheries and Food (MAFF) required livestock on infected farms to be culled within 24 hours of the disease being reported and those on neighbouring farms within 48 hours. Here we investigate whether progress towards meeting these targets has had a detectable impact on the course of the epidemic in the United Kingdom. We conclude that it has now been brought under control, but it will be important to contain rapidly any new outbreaks in previously unaffected areas.

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.