FOOT-AND-MOUTH DISEASE

E. PAUL J. GIBBS

College ofVeterinary Medicine, University ofFlorida, Gaines­ville, Florida, USA

Foot-and-mouth disease (FMD) is caused by a picornavi- rus and is predominantly a disease of domestic ruminants (cattle, sheep and goats) and pigs.

Infectious Diseases of Wild Mammals and Birds in Europe, First Edition. Edited by Dolores Gavier-Widen, J. Paul Duff, and Anna Meredith. © 2012 Blackwell Publishing Ltd. Published 2012 by Blackwell Publishing Ltd.

a disease that is of significant economic, trade and/or food security importance for a considerable number of countries; which can easily spread to other countries and reach epidemic proportions; and where control/management, including exclu­sion, requires cooperation between several countries.

Because of the global concern over FMD and the success of many countries in eradicating the disease, many species of wildlife have been recorded to be susceptible to FMD virus either through natural or experimental infection. When FMD is confirmed in domestic animals, questions inevitably arise as to the role of wildlife in possibly intro­ducing and maintaining the disease. However, with one important exception (the African Cape buffalo (Syncerus caffer)), wildlife species are only occasionally infected with FMD, even when there is an extensive epidemic in domes­ticated livestock.

There are several reports of FMD in wildlife in Europe⁽¹⁾, but most date to the early part of the 20th century, when the disease was endemic in Europe and diagnosis was usually based only on clinical signs.

In summary, although FMD has the potential to cause disease in European wildlife, history indicates that it has never been an important pathogen of wildlife in Europe. Apart from the recent report of the infected wild boar in Bulgaria, there are no recent reports in the English litera­ture of naturally occurring cases of clinical FMD in Euro­pean wildlife that have been confirmed by virus isolation or other techniques, and — in contrast with the situation in Africa — there is no known reservoir of the virus in any wildlife species.

AETIOLOGY

FMD virus is classified within the order Picornavirales, the family Picornaviridae and the genus Aphthovirut, with FMD virus being the type species in the genus and the Greek descriptor Aphtho' referring to vesication, which is the characteristic clinical sign of FMD.

The viral aetiology of FMD (i.e. distinct from bacterial) was established by filtration in 1898 by F.A.J. Loeffler and P. Frosch working with Robert Koch. Foot-and-mouth disease virus was the first virus discovered that affected vertebrates. Since that epochal discovery, FMD virus has been intensively studied. The virus particle is non­enveloped, very small (27 nm in diameter), has an icosa- hedral symmetry and a single-stranded, positive-sense, RNA genome. FMD viruses are relatively resistant and, dependent upon environmental conditions, can survive several days or more on fomites and even longer in animal products; however, FMD viruses are labile at pH values below 6 and above 9, which simplifies disinfection.

X-ray crystallographic analysis of purified virus has shown that the virions are constructed from 60 copies each of four capsid proteins: VP1, VP2, VP3 and VP4. Amino acid substitutions ofVP1, 2, and 3 correlate with antigenic variation.

There are seven serotypes of FMD virus: O, A, C, Asia 1 and SAT 1, SAT 2 and SAT 3. The first FMD serotypes were designated O (Oise) and A (Allemagne) and serotype C was named in the anticipation that a logical alphabetical nomenclature would be established. That was not achieved, although the three serotypes recognized in the South African territories were systematically named.

The serotypes form two groups, as assessed by RNA sequencing with serotypes O, A, C and Asia 1 in one group and the three SAT serotypes in the other. Applying the criteria for recognition of a serotype, infection or vaccina­tion with one virus serotype does not confer protection against another serotype. There is considerable antigenic variation within serotypes, and at one time subtypes were recognized. However, this practice has been replaced by molecular and antigenic comparison of a new isolate to the availability of vaccines within the serotype that will provide clinical protection against infection with the new isolate.

EPIDEMIOLOGY

GEOGRAPHICAL DISTRIBUTION AND HOSTS

The control and eradication of FMD has improved mark­edly in recent years, particularly in Europe and in some countries in Southeast Asia and South America. However, the disease remains endemic and at a high prevalence in many countries in Africa, the Middle East, Asia and South America. The countries of Europe, North and Central America, the Pacific nations and the Caribbean are free of the disease. Serotypes O and A are the most prevalent and occur in parts of South America, North and West Africa, and the Middle East. In recent years, serotype O viruses have spread widely in Asia, infecting countries previously free of disease. These serotype O viruses present a threat to other regions, as exemplified by the pan-Asian serotype O virus that spread first to South Africa and then to Europe in 2000 and 2001, respectively.

Serotypes SAT 1 and 2 are present in several countries in sub-Saharan Africa, with SAT 3 currently restricted to southern Africa. Asia 1 is currently restricted to eastern parts of Asia. Type C is possibly extinct in the wild, the last case being in the rainforest of Brazil. Information on the current geographical distribution of FMD virus sero­types may be found at the World Reference Laboratory for FMD(³), the World Organisation for Animal Health (OIE) website (WAHID)(4) and the Food and Agriculture Depart­ment of the United Nations (FAO) website(⁵).

FMD affects a wide variety of cloven-hoofed domestic species. Although the horse is refractory to infection, cattle, water buffalo, sheep goats, llamas, camels, and swine are susceptible to infection and develop clinical signs of varying severity.

More than 70 species of wildlife in 20 different families have been reported to be susceptible to infection with FMD virus¹-¹’⁶’⁷). Table 11.1 gives further details of the historical record of FMD in wildlife species⁽⁷⁾. Many are historical reports and based only on clinical signs with no confirmatory diagnosis, and several relate to experimental infections (both by injection and direct contact with animals with FMD) even though FMD has never been recorded in that particular wildlife species under natural conditions. Some relate to animals in zoological collec­tions or captive situations where there was close contact with domestic animals. Accordingly, the following descrip­tions will focus on recent reports where there is proven infection with FMD virus in free-living wildlife species.

Antelope are classified within the family Bovidae, so it is not surprising that the most recent and significant reports of clinical FMD infections in free- living wildlife (i.e. as determined by frequency and confirmation of the viral aetiology) are in their loosely defined subfamily.

In terms of geography, most reports of confirmed cases of FMD in free- living species are reported from South Africa — more specifically the Kruger Park, where FMD in wildlife has been studied for many years.

FMD is endemic in domestic livestock in most areas of Africa. The discovery of the persistence of FMD virus in African Cape buffalo in the 1970s has led to many excel­lent epidemiological studies demonstrating that wildlife are an occasional source of infection for domestic cattle. Transmission of FMD virus from Cape buffalo to other species is probably a rare event, as they have been found to be infected in areas where FMD does not occur in cattle. It seems likely that impala, which share watering holes in the dry season with Cape buffalo, become infected and transmit the disease to domestic cattle. Readers wishing to learn more of the ecology and control of FMD in wildlife in Africa should consult Vosloo et al. (2004 and 2009)⁽⁶’⁸⁾.

In an outbreak of FMD in mountain gazelle (Gazella gazelle) in Israel(⁹), where cattle were believed to be the source of the infection, the case fatality rate among the gazelle was over 50%, with at least 1,500 animals dying. Death was considered to be due to myocarditis. Fortu­nately such events are highly unusual, and there have been no further reports of the disease in free-living populations of mountain gazelle.

Historical reports indicate that several species of deer worldwide may be susceptible to FMD, including most of the deer currently found free-living in Europe, but there are no descriptions in the recent literature of the clinical presentation of confirmed FMD in naturally infected deer of any species.

FMD in white-tailed deer in the USA is reported to be similar to that seen in cattle. Although natural cases of

TABLE 11.1 Wild animal species naturally or experimentally susceptible to FMD virus.

(West European)

FMD have never been recorded in American bison (Bison bison'), this species has been shown to be highly susceptible to FMD and under experimental conditions can transmit disease through contact with domestic cattle⁽¹¹⁾.

Although history and experimental studies indicate that many wildlife species should be considered susceptible, until the recent confirmation of FMD in a wild boar in Bulgaria there have been no other reports of FMD in wildlife in Europe since the continental eradication of FMD from domestic livestock in Europe in the 1990s. No confirmed cases of FMD were reported in wildlife species during the extensive FMD epidemic in Northern Europe in 2001. Limited serological surveillance of European wild boar and deer following this epidemic indicated no evi­dence of infection⁽¹²⁾.

The wild boar ( Sus scrofa) is the ancestor of the domestic pig and is therefore closely related. There are historical reports of FMD in wild boar in Europe. In late December 2010, type O FMD virus was identified in samples of vesicular tissue from foot lesions affecting a wild boar in south east Bulgaria. The boar was one of three shot by hunters approximately 2 km from the border with the European area of Turkey, where FMD in domestic animals has been recently reported. Outbreaks of FMD in cattle, sheep, goats and pigs have since been confirmed in the same area of Bulgaria. A limited survey of wild boar in Turkish Thrace indicated that infection had also occurred in this population. Modelling indicates that FMD virus could remain endemic in the wild boar population in the region for up to 2 years. As of May 2011, epidemiological investigation has failed to identify how the wild boar became infected. Wild boar are omnivorous, and ingestion of infected meat inadvertently carried into a country and discarded could theoretically lead to disease in this species. Various reports on the situation can be accessed from the ProMED website⁽¹³⁾.

The same type O FMD virus caused disease in cattle in Northern Israel in spring 2011. There are wild boar popu­lations in Northern Israel and in neighbouring areas of Lebanon and Syria. Although there is no direct evidence that the wild boar were responsible for the introduction of FMD into Israel in 2011, it is reasonable to suggest that they may have been involved. Between 1987 and 1999, according to the data of the Israeli Veterinary Services and the national FMD laboratory, 740 sera were collected from wild boars shot in northern Israel. Of these, 108 (14.6%) were found to have antibody to FMD virus. During the same period, 73 oesophageal tissue samples were collected from hunted boar. Two samples, from boar shot in June 1992, yielded FMD virus serotype O. One of the boar was reported to have had typical FMD lesions on its feet. A later survey of 21 boar hunted in the early months of 2007 revealed that 18 had antibody to the non-structural pro­teins of the FMD virus. Although no virus could be iso­lated from these wild boar, the serology clearly indicated that the boar had been infected with FMD virus. The results also indicated that infection in the boar in one location seems to have taken place sometime before the outbreaks were recorded in the domestic livestock¹-¹³).

EPIDEMIOLOGICAL ROLE OF WILD ANIMALS

Apart from the persistence of FMD in African Cape buffalo in Africa, the disease is not established in any wildlife population in Europe or any other continent.

TRANSMISSION

FMD virus is transmitted to susceptible animals in several ways; through close contact with infected animals and fomites, by inhalation of aerosolized virus and by ingestion of infected meat products. Infected animals produce large amounts of virus in vesicular fluid and in secretions and excretions, such as in milk and faeces, that can contami­nate people’s clothing, vehicles and equipment. The virus titre in vesicular fluid may be in excess of 10,000,000 tissue culture infectious doses per 1 ml (10⁷'° TCID₅₀ per ml). The virus is also present in the exhaled breath of infected animals. Infected pigs produce significantly larger quantities of virus as an aerosol (~10⁶'° TCID₅₀ per hour) than infected cattle, sheep, goats and deer (~ 10^4.0 TCID₅₀ per hour). Cattle may become infected after inhalation by as few as 10 TCID₅₀ of FMD virus. The virus concentra­tion needed to infect animals by ingestion is much higher (~103.⁰ TCID₅₀ per ml).

PATHOGENESIS, PATHOLOGY AND IMMUNITY

DOMESTIC ANIMALS

The main route of infection with FMD virus is through inhalation of droplets, but ingestion of infected food, inoculation with contaminated vaccines, insemination with contaminated semen and contact with contaminated clothing and veterinary instruments can all produce infec­tion. In animals infected via the respiratory tract, initial viral replication occurs in the pharynx and respiratory bronchioles, followed by viraemic spread to other tissues and organs before the onset of clinical disease. Viral excre­tion commences about 24 hours before the onset of clini­cal disease and continues for several days. Aerosols produced by infected animals contain large amounts of virus, particularly those produced by swine. Large amounts of virus are also excreted from ruptured vesicles and in milk. FMD virus may persist in the pharynx of some animals for a prolonged period after recovery. In cattle, virus may be detectable for periods up to 2 years after exposure to infection; in sheep for about 6 months. Viral persistence does not occur in swine. The mechanisms by which the virus produces a persistent infection in rumi­nants are unknown. The virus is present in the pharynx in an infectious form, because if pharyngeal fluids are inocu­lated into susceptible animals they develop FMD. Attempts to demonstrate that carrier cattle can transmit disease by placing them in contact with susceptible animals have given equivocal results.

WILDLIFE SPECIES

There have been no specific studies of the pathogenesis of FMD in wildlife species. Experimental infections of the larger species of deer found in Europe, mentioned earlier, indicate that the pathogenesis is similar to that of FMD in other ruminants, particularly sheep and goats. Fallow and sika deer become persistently infected with infectious FMD virus, which is recovered from the pharynx of some animals for several months after infection, i.e. they become carriers¹-²). Red deer only occasionally became carriers. The smaller species of deer (muntjac and roe deer) do not become carriers. Of the various African antelope suscepti­ble to FMD virus, kudu, wildebeest and sable can become persistently infected, but impala do not(¹).

The African Cape buffalo was first discovered to be persistently infected with FMD virus in the 1970s(⁶). Since then, persistence of the three SAT serotypes of FMD virus in African buffalo has been extensively studied, and it is recognized that the species is a major reservoir of all three serotypes; however, not all African buffalo populations are infected with FMD virus. The different serotypes are maintained in the infected buffalo herds in the absence of any contact with infected domestic cattle. Individual animals may harbour more than one serotype.

FMD is characterized by vesicles (blisters or aphthae) at multiple sites, generally at points of pressure or mechanical stress, such as the mouth and the feet. The oral lesions in cattle can be extensive, and the entire epithelium of the tongue may be desquamated naturally or be detached as a ‘slipper’ when the tongue is manually exteriorized for examination. Vesicles in the mouth quickly rupture, expos­ing an eroded area. However, healing is generally rapid, with the epithelium being completely regenerated within a week. Ruptured vesicles present in the interdigital cleft of the feet commonly become infected with bacteria and healing may be more protracted. Vesiculation of the coro­nary band can lead to defects in the growth of the horn. At necropsy, ruptured vesicular lesions may be seen affect­ing the pillars of the rumen. Young animals that die of myocarditis may exhibit ‘tiger heart’ striping, which is characterized histologically by myocardial degeneration and necrosis. (For images of FMD lesions in domestic animals at various times after onset see(⁵).)

Histologically, FMD vesicles extend only to the stratum spinosum of the epithelium and begin as clusters of hyper- eosinophilic degenerating keratinocytes, which lead to the accumulation of intercellular oedema. Similar pathology may be seen in wildlife. Pancreatitis was reported in the mountain gazelle that died of FMD in Israel.

Recovery from clinical FMD is correlated with the development of antibody. The early IgM antibodies neu­tralize the homologous type of virus and may also be effective against heterologous types. By contrast, the IgG produced during convalescence is type-specific. Cattle that have recovered from FMD are usually immune to infec­tion with the same virus type for a year or more, but immunity is not considered life-long. Recovered animals, however, can be immediately infected with one of the other types of FMD virus and develop clinical disease.

Clinical signs

DOMESTIC ANIMALS

I n general, clinical signs are most severe in cattle and swine, but outbreaks have been reported in swine, whereas cattle in close contact with them did not develop clinical disease. The disease in sheep and goats is often mild and subclinical. In cattle, after an incubation period of 2—8 days, there is fever, loss of appetite, depression and a marked drop in milk production. Within 24 hours, drool­ing of saliva commences and vesicles develop on the tongue and gums. Cattle often open and close their mouths with a characteristic smacking sound. Vesicles may also be found in the interdigital skin and coronary band of the feet and on the teats. The vesicles soon rupture, producing large denuded erosive lesions. Those on the tongue often heal within a few days, but those on the feet and within the nasal cavities often become secondarily infected with bacteria, resulting in prolonged lameness and a mucopu­rulent nasal discharge. In calves up to 6 months of age, FMD virus can cause death through myocarditis. The mortality in adult cattle is very low, but although the virus does not cross the placenta, cattle may abort, presumably as a consequence of fever. Also, affected animals become non-productive or poorly productive for long periods. They may eat little for a week after the onset of clinical signs and are often very lame; and mastitis and abortion lower milk production further. In endemic areas, where cattle may have partial immunity, the disease may be mild or subclinical.

In swine, lameness is often the first sign of FMD. Foot lesions can be severe and may be sufficiently painful to prevent the pig from standing. Denuded areas between the claws usually become infected with bacteria; this causes suppuration and in some cases loss of the claw and pro­longed lameness. Vesicles within the mouth are usually less prominent than in cattle, although large vesicles, which quickly rupture, often develop on the snout.

The severity of the clinical disease in sheep and goats is dependent upon the strain of the virus, the breed of the animal and environmental conditions. In general, the disease is usually milder than in cattle and is principally characterized by foot lesions accompanied by lameness. The mortality rates in young lambs and kids may be high.

WILDLIFE SPECIES

As there are no recent descriptions of naturally occurring clinical FMD in wildlife species in Europe, the following descriptions are based on the experimental studies men­tioned earlier(²). The clinical appearance of lesions and the severity of the disease were not affected by the route of infection (inoculation or contact), but were species­dependent. FMD in roe and muntjac deer was similar and severe, with elevated temperatures and development of generalized disease; some animals died. There were no subclinical infections. Vesicular lesions developed on the dental pad and tongue and between the claws of the feet. In contrast with the severe disease seen in the roe and muntjac deer, disease in the red, fallow and sika deer was generally mild and similar to that seen in sheep. Small vesicles developed on the tongue and dental pad of some deer and in the interdigital cleft and bulbs of the heel. Colour photographs from the above studies of the disease in roe, muntjac, fallow and sika deer may be found at The Deer Initiative(¹⁴).

The lesions of FMD reported in antelope in Africa are similar to domestic livestock. The severity of clinical disease in impala can be highly variable and many are only subclinically affected. Lameness is the most likely clinical indicator of disease, as affected antelope rarely exhibit excessive salivation, even when there are lesions in the mouth. Animals that have recovered from FMD may show faults in the hoof wall as the hoof grows. This may be used in impala to estimate when infection occurred, as it usually takes 5—6 months for the defect to grow out.

DIAGNOSIS

Any vesicular disease in domestic or free-living artiodac- tyla, or a history of sudden death in a large number of young cloven- hoofed animals, should immediately raise concern that it could be FMD. Failure to act can be dis­astrous, as an epidemic may quickly generate.

The acronym for foot-and-mouth disease — FMD — also denotes an important characteristic of the epidemiology that directly relates to diagnosis, namely that of a ‘fast­moving disease’. The incubation period is frequently no more than 2—3 days, and virus is highly infectious; hence rapid diagnosis of FMD is of paramount importance for early containment of the outbreak. This is particularly important in countries and regions normally free of infection.

While the history of the disease and the involvement of different species may be valuable pointers during the field investigation, there are other diseases that can be clinically confused with FMD, and thus it is not uncommon for specimens to be collected for laboratory diagnosis. Speci­mens are usually couriered in person to the laboratory to minimize delay. National and international laboratories that are designated as reference centres for the diagnosis of FMD are on constant standby and, when alerted, examine samples immediately upon arrival.

The portfolio of laboratory tests currently in use to diagnose FMD is very sophisticated. The OIE Terrestrial Manual 2009 describes in detail those tests that are inter­nationally recognized for the diagnosis of FMD(4). Tests based on the reverse transcription polymerase chain reac­tion (RT- PCR) are used in parallel with enzyme- linked immunosorbent assays (ELISA) to confirm that the disease is caused by FMD virus and to identify which serotype is involved. Assuming the samples were collected from animals in the early stages of disease and were appropri­ately protected in transit to the laboratory, a diagnosis can be available within a few hours of receipt. Laboratories that are equipped to conduct sequencing of the gene product generated by the RT-PCR tests can usually generate sequence data within 24 hours that are of epidemiological value. The lineage of the virus can often be deduced from the sequence data and thus gives pointers to: i) the most likely source of the virus; and ii) the closest vaccine match. Although the isolation and characterization of the virus in cell culture remains the diagnostic ‘gold standard’, confir­mation of an outbreak of FMD is now based on the results of RT-PCR and ELISA technology.

For serological surveillance, a variety of ELISA are available⁽⁴⁾.

MANAGEMENT, CONTROL AND REGULATIONS

FMD is a reportable disease in most countries (i.e. there is a legal responsibility on owners of stock and land to report any suspicion). Upon receiving such reports, the state veterinary authorities of most countries will immedi­ately dispatch a veterinarian trained in the clinical recogni­tion of foreign animal diseases to examine the affected animals. Because FMD virus is so easily spread by con­taminated instruments, clothing, etc., care must be taken to avoid inadvertent spread of virus from affected animals while waiting for the diagnostician to arrive. Boots and equipment should be disinfected. Rather than move any dead animals, it is better to protect them from scavengers and leave them at the site where they were found. The movement of apparently normal animals away from the area should be prevented, and visits by people should be controlled until a diagnosis is established.

Notwithstanding the wide range of species that are con­sidered susceptible to FMD virus, viewed globally, the epidemiology of FMD indicates that wildlife species are only rarely affected. With the exception of the African Cape buffalo in sub-Saharan Africa, there is no reservoir of FMD virus in any other wildlife species. Other than in situations that can be linked to African Cape buffalo, FMD in wildlife is an extension of disease in livestock.

The control of FMD both in domestic animals and wildlife depends upon the FMD status of the country. When FMD occurs in countries and regions normally free of FMD, the attention of the veterinary authorities to wildlife is secondary to controlling and eradicating disease in the domestic livestock. Where the disease is endemic in domestic livestock, such as in parts of Asia, South America and Africa, little attention may be given by the veterinary authorities to any possible cases of FMD in wildlife.

There are many routes by which FMD virus can enter a country free of FMD. In contrast to humans, who are generally free to travel between countries without extensive health checks, the international movement of domestic livestock and ungulate wildlife is strictly regulated and often forbidden. Nowadays, most introductions of FMD to non-endemic countries can be traced to the uninten­tional feeding of infected meat products to domestic pigs. If the disease goes unnoticed and spreads rapidly within the pig population on the affected farm, a large volume of aerosolized virus is generated and is blown as a plume to infect susceptible livestock downwind. This was the series of events that led to the 2001 epidemic of FMD in the UK and other European countries.

As mentioned previously, cattle may become infected after inhalation by as few as 10 TCID₅₀ of FMD virus. Although sheep, goats and deer have similar susceptibility to aerosolized FMD virus, they have a smaller respiratory volume than cattle and are less likely to be infected when the concentration of virus in the plume is low. However, once infected, the disease in these smaller ruminants is less likely to be noticed clinically.

While the evidence implicating wild boar in the intro­duction of FMD into Bulgaria and Israel is circumstantial, these incidents and the increase in boar populations across Europe justify increased surveillance for FMD in wildlife.

In Western Europe, most attention is given to FMD in deer. The larger herding species of free-living deer, particu­larly red, fallow and sika, often share common pastures with cattle and sheep. The smaller species, such as roe and muntjac, are more secretive and if affected with FMD are more likely to seek cover than graze pastures. During the time when disease is active in the domestic livestock,

observation of wildlife for clinical signs suggestive of FMD is important, but it is generally accepted that more aggres­sive surveillance in the absence of any concern is unwar­ranted and more likely to spread disease by dispersing potentially infected deer. When the disease has been con­trolled in the domestic livestock, selected populations of those wildlife species considered to be susceptible to FMD should be examined for any prior or current evidence of subclinical infection.

PUBLIC HEALTH CONCERN

FMD has been reported to affect humans, but the disease is benign and there have been very few cases. FMD is characterized by fever, anorexia and the development of vesicular lesions at the site of viral exposure (e.g. skin abra­sions) or systemically on the hands and feet and in the mouth. No cases of human FMD were reported during the extensive 2001 epidemic in Europe. The disease of hand, foot and mouth disease, as seen predominantly in children, is caused by a different virus from FMD virus.

SIGNIFICANCE AND IMPLICATIONS FOR ANIMAL HEALTH

There is no question that under natural conditions several free-living wildlife species are: i) susceptible to infection with FMD virus; ii) can develop clinical disease; iii) are capable of transmission of FMD virus to domestic species; and iv) can represent a reservoir of FMD virus through persistent infection.

The reservoir of FMD virus in African Cape buffalo is of economic concern to several countries in sub-Saharan Africa, as they develop an export market for beef. There is no known or suspected wildlife reservoir of FMD virus other than the African Cape buffalo. Apart from southern Africa, the disease rarely affects wildlife, and when it does it is an extension of disease in domestic livestock.