John Gloster

Integrating genetic and epidemiological data to determine transmission pathways of foot-and-mouth disease virus

Estimating detailed transmission trees that reflect the relationships between infected individuals or populations during a disease outbreak often provides valuable insights into both the nature of disease transmission and the overall dynamics of the underlying epidemiological process. These trees may be based on epidemiological data that relate to the timing of infection and infectiousness, or genetic data that show the genetic relatedness of pathogens isolated from infected individuals. Genetic data are becoming increasingly important in the estimation of transmission trees of viral pathogens due to their inherently high mutation rate. Here, we propose a maximum-likelihood approach that allows epidemiological and genetic data to be combined within the same analysis to infer probable transmission trees. We apply this approach to data from 20 farms infected during the 2001 UK foot-and-mouth disease outbreak, using complete viral genome sequences from each infected farm and information on when farms were first estimated to have developed clinical disease and when livestock on these farms were culled. Incorporating known infection links due to animal movement prior to imposition of the national movement ban results in the reduction of the number of trees from 41 472 that are consistent with the genetic data to 1728, of which just 4 represent more than 95% of the total likelihood calculated using a model that accounts for the epidemiological data. These trees differ in several ways from those constructed prior to the availability of genetic data.

Molecular Epidemiology of the Foot-and-Mouth Disease Virus Outbreak in the United Kingdom in 2001

ABSTRACT The objective of this study was to quantify the extent to which the genetic diversity of foot-and-mouth disease virus (FMDV) arising over the course of infection of an individual animal becomes fixed, is transmitted to other animals, and thereby accumulates over the course of an outbreak. Complete consensus sequences of 23 genomes (each of 8,200 nucleotides) of FMDV were recovered directly from epithelium tissue acquired from 21 farms infected over a nearly 7-month period during the 2001 FMDV outbreak in the United Kingdom. An analysis of these consensus sequences revealed very few apparently ambiguous sites but clear evidence of 197 nucleotide substitutions at 191 different sites. We estimated the rate of nucleotide substitution to be 2.26 × 10−5 per site per day (95% confidence interval [CI], 1.75 × 10−5 to 2.80 × 10−5) and nucleotide substitutions to accrue in the consensus sequence at an average rate of 1.5 substitutions per farm infection. This is a sufficiently high rate showing that detailed histories of the transmission pathways can be reliably reconstructed. Coalescent methods indicated that the date at which FMDV first infected livestock in the United Kingdom was 7 February 2001 (95% CI, 20 January to 19 February 2001), which was identical to estimates obtained on the basis of purely clinical evidence. Nucleotide changes appeared to have occurred evenly across the genome, and within the open reading frame, the ratio of nonsynonymous-to-synonymous change was 0.09. The ability to recover particular transmission pathways of acutely acting RNA pathogens from genetic data will help resolve uncertainties about how virus is spread and could help in the control of future epidemics.

Bluetongue in the United Kingdom and northern Europe in 2007 and key issues for 2008

As predicted, bluetongue arrived in the UK in 2007. Here, John Gloster and colleagues investigate the meteorological parameters that allowed this incursion into the UK and discuss key issues related to the diseases possible re-establishment in 2008.

Airborne transmission of foot-and-mouth disease virus from Burnside Farm, Heddon-on-the-Wall, Northumberland, during the 2001 epidemic in the United Kingdom.

The results of a detailed assessment of the atmospheric conditions when foot-and-mouth disease (FMD) virus was released from Burnside Farm, Heddon-on-the-Wall, Northumberland at the start of the 2001 epidemic in the UK are consistent with the hypothesis that the disease was spread to seven of the 12 farms in the immediate vicinity of the source by airborne virus, and airborne infection could not be ruled out for three other premises; the remaining two premises were unlikely to have been infected by airborne virus. The distances involved ranged from less than 1 km up to 9 km. One of the farms which was most probably infected by airborne virus from Burnside Farm was Prestwick Hall Farm, which is believed to have been key to the rapid spread of the disease throughout the country. In contrast, the results of detailed atmospheric modelling, based on a combination of clinical evidence from the field and laboratory experiments have shown that by assuming a relationship between the 24-hour average virus concentrations and subsequent infection, threshold infection levels were seldom reached at the farms close to Burnside Farm. However, significant short-term fluctuations in the concentration of virus can occur, and short-lived high concentrations may have increased the probability of infection and explain this discrepancy.

A new algorithm quantifies the roles of wind and midge flight activity in the bluetongue epizootic in northwest Europe

The 2006 bluetongue (BT) outbreak in northwestern Europe had devastating effects on cattle and sheep in that intensively farmed area. The role of wind in disease spread, through its effect on Culicoides dispersal, is still uncertain, and remains unquantified. We examine here the relationship between farm-level infection dates and wind speed and direction within the framework of a novel model involving both mechanistic and stochastic steps. We consider wind as both a carrier of host semio-chemicals, to which midges might respond by upwind flight, and as a transporter of the midges themselves, in a more or less downwind direction. For completeness, we also consider midge movement independent of wind and various combinations of upwind, downwind and random movements. Using stochastic simulation, we are able to explain infection onset at 94 per cent of the 2025 affected farms. We conclude that 54 per cent of outbreaks occurred through (presumably midge) movement of infections over distances of no more than 5 km, 92 per cent over distances of no more than 31 km and only 2 per cent over any greater distances. The modal value for all infections combined is less than 1 km. Our analysis suggests that previous claims for a higher frequency of long-distance infections are unfounded. We suggest that many apparent long-distance infections resulted from sequences of shorter-range infections; a ‘stepping stone’ effect. Our analysis also found that downwind movement (the only sort so far considered in explanations of BT epidemics) is responsible for only 39 per cent of all infections, and highlights the effective contribution to disease spread of upwind midge movement, which accounted for 38 per cent of all infections. The importance of midge flight speed is also investigated. Within the same model framework, lower midge active flight speed (of 0.13 rather than 0.5 m s−1) reduced virtually to zero the role of upwind movement, mainly because modelled wind speeds in the area concerned were usually greater than such flight speed. Our analysis, therefore, highlights the need to improve our knowledge of midge flight speed in field situations, which is still very poorly understood. Finally, the model returned an intrinsic incubation period of 8 days, in accordance with the values reported in the literature. We argue that better understanding of the movement of infected insect vectors is an important ingredient in the management of future outbreaks of BT in Europe, and other devastating vector-borne diseases elsewhere.

Will bluetongue come on the wind to the United Kingdom in 2007

In 2006, over 2000 cases of bluetongue were recorded in northern Europe. The disease, which has been more typically associated with Mediterranean areas, is believed to have become established hundreds of kilometres to the north of its traditional area, probably as a consequence of the hottest summer/autumn period since records began. In this special article, John Gloster and colleagues describe the meteorological conditions surrounding the 2006 outbreak, and investigate the possibility of bluetongue virus (btv) spreading on the wind to the uk in 2007. For this to happen there would need to be a source of windborne virus, together with a susceptible population of ruminants in the vicinity of the coast. Evidence from outbreaks in the Mediterranean Basin suggests that long-distance transport of btv-infected vectors has already occurred, at least in that region. The overall likelihood of this occurring in northern Europe depends critically on whether the virus overwinters on the near continent; this will not be known until around May 2007. The 2006 outbreak has highlighted the importance of understanding the impact of climate change on animal disease.

Normal variation in thermal radiated temperature in cattle: implications for foot-and-mouth disease detection

BackgroundThermal imagers have been used in a number of disciplines to record animal surface temperatures and as a result detect temperature distributions and abnormalities requiring a particular course of action. Some work, with animals infected with foot-and-mouth disease virus, has suggested that the technique might be used to identify animals in the early stages of disease. In this study, images of 19 healthy cattle have been taken over an extended period to determine hoof and especially coronary band temperatures (a common site for the development of FMD lesions) and eye temperatures (as a surrogate for core body temperature) and to examine how these vary with time and ambient conditions.ResultsThe results showed that under UK conditions an animals hoof temperature varied from 10°C to 36°C and was primarily influenced by the ambient temperature and the animals activity immediately prior to measurement. Eye temperatures were not affected by ambient temperature and are a useful indicator of core body temperature.ConclusionsGiven the variation in temperature of the hooves of normal animals under various environmental conditions the use of a single threshold hoof temperature will be at best a modest predictive indicator of early FMD, even if ambient temperature is factored into the evaluation.

Airborne spread of foot-and-mouth disease - model intercomparison.

Foot-and-mouth disease virus (FMDV) spreads by direct contact between animals, by animal products (milk, meat and semen), by mechanical transfer on people or fomites and by the airborne route, with the relative importance of each mechanism depending on the particular outbreak characteristics. Atmospheric dispersion models have been developed to assess airborne spread of FMDV in a number of countries, including the UK, Denmark, Australia, New Zealand, USA and Canada. These models were compared at a Workshop hosted by the Institute for Animal Health/Met Office in 2008. Each modeller was provided with data relating to the 1967 outbreak of FMD in Hampshire, UK, and asked to predict the spread of FMDV by the airborne route. A number of key issues emerged from the Workshop and subsequent modelling work: (1) in general all models predicted similar directions for livestock at risk, with much of the remaining differences strongly related to differences in the meteorological data used; (2) determination of an accurate sequence of events on the infected premises is highly important, especially if the meteorological conditions vary substantially during the virus emission period; (3) differences in assumptions made about virus release, environmental fate and susceptibility to airborne infection can substantially modify the size and location of the downwind risk area. All of the atmospheric dispersion models compared at the Workshop can be used to assess windborne spread of FMDV and provide scientific advice to those responsible for making control and eradication decisions in the event of an outbreak of disease.

Re-emergence of bluetongue in northern Europe in 2007.

BLUETONGUE is a disease of ruminants caused by bluetongue virus (BTV), which is transmitted by Culicoides species midges. Although hosts may remain infectious for a period of several months, in temperate regions the activity of Culicoides species drops to negligible levels during the winter, and this often results in the apparent extinction of outbreaks. However, the disease has been known to reappear after months with no detectable transmission, a phenomenon termed ‘overwintering’ (Osmani and others 2006). Several possible mechanisms for this phenomenon have been suggested, including vertical transmission in the vector (White and others 2005) and persistent infection of host T cells (Takamatsu and others 2003). However, none has been confirmed in the field, and the process remains poorly understood. Although bluetongue has historically been absent from Europe, outbreaks have occurred with increasing frequency in southern Europe since the late 1990s. This spread is thought to have been a consequence of climate change (Purse and others 2005). In August 2006, the first cases of bluetongue in northern Europe were reported near Maastricht, the Netherlands, and during the course of the resulting outbreak over 2000 holdings were affected in the Netherlands and in Belgium, France, Germany and Luxembourg (Elbers and others 2007). Reports of new cases declined after mid-October, and the last clinical case was reported on January 15, 2007 (Losson and others 2007), although several earlier outbreaks were retrospectively reported as a result of ongoing serological investigations (EFSA Epidemiology Working Group 2007). On June 16, 2007, the first case of BTV seroconversion in northern Europe during the 2007 season was reported in blood taken from a sentinel animal on a holding in North Rhine-Westphalia, Germany, in early May (International Society for Infectious Diseases 2007). BTV serotype 8 (BTV-8) seroconversion occurs approximately six to 10 days after infection (Darpel and others 2007), suggesting that infection was likely to have occurred before the end of April. The holding had previously been infected during the 2006 epidemic. By July, several further cases had been reported from the same region, as well as from France, Belgium and the Netherlands. The serotype was confirmed as BTV-8, suggesting that overwintering had occurred, although it was not then absolutely known whether the new cases had resulted from a resumption of transmission of overwintering BTV-8, iatrogenic infection (infection resulting from a medical procedure, for instance, vaccination), reintroduction, or some other source. At low temperatures, the longevity of midges may be much greater (Mellor and Leake 2000). At the same time, the rate of BTV replication is highly dependent on ambient temperature, and replication in the poikilothermic vector may be greatly retarded or even stopped by cold weather (Wittmann and others 2002). Small numbers of adult Culicoides species were caught throughout the winter of 2006/07 in Belgium within the region of the outbreak, although it was not clear whether these were overwintering or newly emerged adults (Losson and others 2007). Consequently, in temperate regions, it appears theoretically possible that midges infected towards the end of a previous transmission season or during the winter may survive for long periods, but will not become capable of transmitting the virus until rising temperatures during the following spring enable the virus to replicate to sufficient levels. The aim of this study was to determine whether this hypothesis is capable of predicting the timing of re-emergence of BTV-8 in northern Europe during the 2007 season. Different BTV serotypes and strains respond differently to temperature, and data on the relationship between temperature and the completion of the extrinsic incubation period (EIP) for the BTV-8 strain involved in the north European outbreak are not yet available. However, because it is likely to be adapted for replication in cooler temperatures, and

Clinical and laboratory investigations of the outbreaks of foot-and-mouth disease in southern England in 2007

A case of foot-and-mouth disease (fmd) on a cattle farm in Normandy, Surrey, was confirmed on Friday August 3, 2007, the first case in the uk since 2001. The infection was detected nearby on a second farm on August 6. On September 12, fmd was confirmed on a farm approximately 20 km from Normandy in Egham, and this was followed by cases on five more farms in that area in the next three weeks. The majority of the infected farms consisted of multiple beef cattle holdings in semi-urban areas. In total, 1578 animals were culled on the infected farms, and fmd virus infection was confirmed in 278 of them by the detection of viral antigen, genome or antibodies to the virus, or by clinical signs. This paper describes the findings from animal inspections on the infected farms, including the estimated ages of the fmd lesions and the numbers of animals infected. It also summarises the test results from samples taken for investigation, including the detection of preclinically viraemic animals by using real-time reverse transcriptase-pcr.