FMD is a highly contagious viral vesicular disease of cloven-hoofed animals. Although seldom lethal in adult animals, it causes serious production losses and is a major constraint to international trade in livestock and livestock products. Severe mortality may occur in young stock, particularly lambs and piglets.
FMD is endemic and at a high prevalence in many countries in Africa, the Middle East and Asia and is also present in parts of South America. Europe, North and Central America, the Pacific nations and the Caribbean are free from the disease.
During the past decade, distribution of the various serotypes has been reported as follows: type O - Asia, parts of Africa and South America, with recent incursions into the United Kingdom and parts of western Europe; type A - Asia, parts of South America and Africa; type Asia 1 - Asia and southeastern Europe; type SAT 1 - Africa and the Arabian Peninsula; type SAT 2 - Africa and the Arabian Peninsula; type SAT 3 - southern Africa; and type C - South Asia and eastern Africa.
The evolution of the pandemic Pan-Asia strain of type O FMD virus in recent years is a good illustration of the disease's potential for sudden and unanticipated international spread. Since its first identification in northern India in 1990, FMD has spread to Nepal (1993), Saudi Arabia (1994) and thence to most of the Middle East; to Europe (Turkish Eastern Thrace, Bulgaria and Greece) in 1996; Bangladesh (1996); Bhutan (1998); mainland China, Taiwan Province of China, Thailand and Malaysia (1999); the Russian Federation, Mongolia, Republic of Korea, Japan and South Africa (2000); and the United Kingdom, Ireland, France and the Netherlands (2001).
The FMD virus is a member of the Aphthovirus genus of the family Picornaviridae. The virion is non-enveloped, about 25 nm in diameter, and has an icosahedral symmetry. It contains a molecule of single-stranded RNA and 60 copies of each of the four structural polypeptides (VP1, VP2, VP3 and VP4). Of these, VP1 contains antigenic determinants that are important in stimulating neutralizing antibodies in infected hosts.
There are seven serotypes of FMD virus - A, O, C, SAT 1, SAT 2, SAT 3 and Asia 1. All the serotypes produce a disease that is clinically indistinguishable but immunologically distinct. There is no cross-immunity among serotypes. They can be differentiated by various serological tests, including the virus neutralization test (VNT), the complement fixation test (CFT) and enzyme linked immunosorbent assay (ELISA). Within each serotype there is a spectrum of antigenic variation with strains of close or distant relationship to each other. Antigenic variation tends to be greatest within type A. Analysis of strains of FMD virus by antigenic and genetic profiles is important in epidemiological studies and for the selection of the most appropriate vaccine strains for a region where vaccination is practised.
The FMD virus is sensitive to both acid and alkaline conditions. It is most stable at pH 7.4-7.6 but all strains are rapidly inactivated below pH 4 and above pH 11. There is some strain variation at intermediate values, but the major determinant is temperature. The virus will retain infectivity at pH 6.7-9.5 at 4°C or lower, but this range narrows as the temperature rises.
The effect of temperature on viral infectivity is influenced by the suspending medium, with organic matter providing some protection against inactivation. At temperatures below freezing, the virus is stable almost indefinitely. Even at 4°C in simple media the virus retains infectivity for more than one year. Suspensions of virus will retain infectivity for eight to ten weeks at ambient temperatures of about 22°C, and for up to ten days at 37°C. Above this temperature, inactivation is more rapid. For example, 56°C for 30 minutes is sufficient to inactivate most strains of FMD virus.
Sunlight per se has little effect on the virus. Environmental inactivation is related more to the effects of desiccation (less than 60 percent relative humidity) and temperature. Acid and alkaline formulations are the most effective for disinfection.
Of the domestic livestock species, cattle, water buffaloes, pigs, sheep, goats and deer are susceptible to FMD; the disease is generally most severe in cattle and pigs. Camelidae (camels, llamas and vicuñas) have a low susceptibility. Wild cloven-hoofed species are susceptible. Though rare, FMD in elephants, hedgehogs and some rodents has been documented. African buffaloes (Syncerus caffer) commonly become infected with FMD virus of the SAT serotypes, although clinical disease is rarely if ever observed.
Some FMD virus strains have a pronounced predilection for one livestock species or another (e.g. pigs or cattle). Such was the case of the porcinophillic type O strain circulating in recent years in East Asia.
Human infections have been reported but are extremely rare and mild. However, people may harbour the virus in their respiratory tract for more than 24 hours without ever developing clinical disease.
In the environment. The FMD virus can retain infectivity for considerable periods in the environment provided it is protected from desiccation, heat and adverse pH conditions. For example, the virus may survive for 14 days in dry faecal material; six months in slurry in winter; 39 days in urine; 28 days on the surface of soil in autumn; and three days on the surface of soil in summer. Such observations have generally been made in countries with a temperate climate, and these times can be expected to be much shorter in countries with hot climates.
In the host (including pathogenesis of the disease). The respiratory system is the major route of infection in ruminant species, and very small doses of virus can initiate infection. The respiratory route is also the more usual portal of entry for pigs, but these animals are much more susceptible to infection by the oral route than are ruminants. The virus can also enter through abrasions in the skin or the mucosae as a result of injury caused by damage from grass seeds, feeding on rough fodder, foot rot, trauma from milking machines or from fingernails during nose restraint of cattle.
After inhalation, virus-laden droplets are transported by ciliary action to the pharyngeal area. Following primary multiplication in the pharyngeal mucosa and draining lymph nodes, the virus is transported in the bloodstream to secondary sites that include the glandular organs, other lymph nodes, epithelial tissues in and around the mouth and feet, and the mammary glands in females. The vagina and prepuce may also be involved. Cardiac muscle is a secondary target in young animals.
The virus is excreted in large quantities in expired air, in all secretions and excretions (including milk and semen) and from ruptured vesicles. Pigs liberate vast quantities of airborne virus in their expired breath - about 3 000 times as much as cattle.
Excretion of the FMD virus can begin up to four days before clinical disease becomes apparent, and this is of great epidemiological significance. Most excretion of the virus ceases four to six days after the appearance of vesicles, when circulating antibodies develop. The virus tends to persist in foot lesions for a day or two longer than in mouth lesions, so that foot lesions may be a better source of virus for diagnostic purposes in older cases. The FMD virus has been detected in the milk and semen of experimentally infected cattle for 23 and 56 days respectively.
After clinical recovery, up to 80 percent of ruminant animals may become persistently infected. This situation is termed the "carrier state" and is defined as carriage of the virus beyond 28 days after primary infection. Such persistent infection is established in the pharyngeal and cranial oesophageal tissues. The duration of the carrier state varies with the host species, strain of virus and possible other factors. The maximum reported carrier periods for different species are three and a half years for cattle; nine months for sheep; four months for goats; and five years or more for African buffaloes. The virus can be recovered intermittently from such animals by oesophageal-pharyngeal (OP) probang collections. The quantity and frequency of virus that can be collected decline progressively with time. Deer, antelopes and llamas either fail to become carriers or carry the virus for only short periods. Little is known as to whether there is a carrier state in water buffaloes. Pigs do not become long-term carriers, and cease excreting the virus within three to four weeks of becoming infected.
In animal products. Although the FMD virus is inactivated in the meat of carcasses that undergo the normal post-slaughter acidification processes, it can retain infectivity for very long periods in frozen or chilled lymph nodes, bone marrow and residual blood clots, and for shorter periods in offal. Other products in which the virus can retain infectivity for long periods include uncooked salted and cured meats, green-salted hides, unpasteurized milk and some other dairy products.
FMD is perhaps the most contagious of animal diseases. Pigs are regarded as important amplifying hosts for the disease because of their ability to be infected orally and their capacity to excrete large quantities of virus in their exhaled breath. Cattle are regarded as good indicator hosts because of their extreme sensitivity to infection by the respiratory route, and the usual development of severe, classical clinical signs in these animals. Sheep have been thought of as maintenance hosts because infection with some virus strains can spread through flocks with little overt sign of disease. It must be stressed that not all FMD viruses will behave in the same way epidemiologically nor will they all have the same host range.
The disease may be transmitted in many ways, including:
Direct contact. FMD can be readily spread by direct contact between infected and susceptible animals, and this is by far the most significant mode of transmission. Stocking density is a determinant of the rate of spread of the disease, which may spread extremely rapidly in intensive farming areas because of high stocking density and the level of challenge from both infected animals and the environment. Conversely, disease spread in extensive grazing areas in hotter climates can be more insidious. Levels of protection (either from convalescence or vaccination) can dampen the movement of viruses in a herd or flock. Congregation of animals, for example at common watering-points, at gatherings for vaccination, dipping, shearing, etc. or through transhumance or nomadism, favours spread of the disease to new herds and areas. The disease can also be disseminated very rapidly by movement of infected animals through livestock markets and shows. In this context, animals that are excreting virus but have not yet developed obvious lesions are particularly significant. The role of persistently infected animals in the transmission of FMD has been uncertain. Transmission from carrier to susceptible cattle has not been demonstrated experimentally. However, there is evidence from Africa of transmission of the virus from carrier buffaloes and cattle under field conditions. This requires close contact and is probably a rare event.
Indirect transmission. The FMD virusis easily spread mechanically by a variety of fomites including animal foodstuffs, bedding, equipment, livestock holding areas, vehicles (particularly the transport compartment of livestock vehicles), clothing, etc. that have been contaminated with infected secretions and excretions (saliva, milk, faeces and urine). Climatic and environmental factors will determine how long the virus will persist on fomites. Veterinarians and other workers who have close contact with livestock are at risk of carrying the virus from farm to farm.
Swill feeding of pigs. Uncooked swill that contains virus-contaminated meat scraps or dairy products has a high potential for spreading infection. Swill originating from aircraft and ships has been incriminated as a major source of infection and has been responsible for a number of cases of international spread of the disease.
Windborne spread. Infection by wind over considerable distances in temperate climates is believed to have occurred in several outbreaks in Europe. Although most windborne spread over land is confined to 10 km, a spread over water of 250 km may have occurred in the case of the Isle of Wight outbreak in 1981. The pattern of windborne spread has generally been from pigs at source to cattle downwind, and is likely to occur only when there are high concentrations of the appropriate livestock species at these locations. Additionally, the following climatic conditions are required: slow and steady wind speed and direction, high relative humidity (optimally above 60 percent), weak sunlight and absence of heavy rain. Long-distance windborne transmission has not been observed in Africa, the Middle East, Asia or Latin America.
Artificial breeding. Transmission of the FMD virus can occur through artificial insemination using infected semen. However, embryo transplantation using properly collected and washed embryos with intact zona pellucidas (using protocols described by the International Embryo Transfer Society [IETS]) does not constitute a risk.
The introduction of the virus (or a new serotype) to previously free herds, areas or countries is likely to lead to a very rapidly spreading epidemic with high morbidity rates.
The epidemiological pattern of the disease tends to be different in temperate and tropical/semitropical parts of the world. In the former, the greater survival of the virus in the environment means that indirect transmission through fomites may be as important as direct contact between infected and susceptible animals. Windborne virus spread is possible under some environmental circumstances.
On the other hand, in hotter climates indirect means of transmission assume less relative importance than direct means of transmission. It is often the movement of potentially infected animals and livestock trading patterns that provides the key to understanding the epidemiology of FMD in such areas.
The incubation period in naturally acquired disease is variable and depends mainly on the animal species, strain of virus, exposure dose and route of entry. It may be as short as two to three days, but can be as long as 10-14 days with very low doses of virus. The incubation period for index cases in an outbreak tends to be longer than for subsequent cases; it may be as short as 18-24 hours when the disease is experimentally produced.
The first indication of the disease is a fever (to 42°C), which is accompanied by severe depression, inappetence and a sudden cessation of milk production. This is followed within a day or so by the development of vesicles, the predilection sites for which are the tongue, lips, gums, dental pad, nares, interdigital skin of the feet, coronary bands, bulbs of the heels and teats of milking animals. Occasionally vesicles appear inside the nostrils or on the muzzle, ocular canthae prepuce or vulva. The lesions begin as small hyperaemic foci at one or more of these sites. Lesions very quickly progress to vesicles initially 1-2 cm in diameter but that rapidly enlarge and often coalesce. They are filled with a clear straw-coloured fluid and their overlying epithelium is blanched. The vesicles rupture within 24 hours to leave raw, painful ulcers surrounded by ragged tags of necrotic epithelium.
In the mouth, vesicles are particularly prominent on the tongue, dental pad and gums. In severe cases, most of the mucosa of the dorsal surface of the tongue may slough. The painful stomatitis associated with unruptured and freshly ruptured vesicles causes excess salivation, lip smacking and cessation of eating. There is rapid loss of body condition. In uncomplicated cases, mouth lesions heal fairly rapidly over about a ten-day period and eating may resume within a few days of rupture of vesicles.
Acute lameness and reluctance to move accompany foot lesions, and secondary infections may lead to severe involvement of the deeper structures of the foot. The inability to move may lead to severe dehydration, loss of body weight, and debilitation as affected animals cannot cover distances to drink or eat. Teat lesions may also be complicated by secondary mastitis.
Although there is a very high morbidity rate, the mortality rate in adult animals is generally less than 5 percent. There is often a prolonged convalescence with significant losses of meat and milk production, and of draught power. Pregnant animals may abort. Long-term sequelae may include foot deformities and permanent damage to the udder. Occasionally, endocrine gland damage leads to heat intolerance and a chronic "panting" syndrome characterized by dyspnoea and ill thrift.
Infection of very young calves may cause sudden death, without vesicular lesions, as a result of cardiac lesions. The mortality rate in such animals can be 50 percent or even higher, aggravated by the fact that milk production in affected dams is diminished or will not allow the offspring to nurse.
Highly productive animals tend to suffer more severely. The clinical signs of FMD in native breeds of cattle in endemic areas are usually milder than those described above.
Early signs of FMD in pigs include fever, inappetence and reluctance to move. The most pronounced vesicles are on the feet. These vesicles cause acute lameness, pain and recumbency, particularly if the pigs are housed on a hard floor. Pigs may walk on their knees. However, the disease is sometimes difficult to detect when affected pigs are housed on soft bedding. Vesicles may occur on the coronets, interdigital skin, dew claws or bulbs of the heel. Lesions may also develop on the knees and hocks. Vesicles that encircle the coronet may lead to separation of the keratinized layers of the hoof from the corium. In severe cases there may be sloughing of the hoof. Otherwise, a line of separation between old and new horn moves steadily down the hoof at a rate of about 1 mm a week, starting a week after the rupture of coronary band vesicles. The age of FMD lesions in pigs can often be estimated in this way.
Vesicles often occur on the snout. Usually there is a single large vesicle on the dorsum of the snout behind the nasal rostrum. Vesicles on the tongue are relatively uncommon in pigs, and when they occur are small and heal rapidly.
Sows often develop vesicles on their teats. Pregnant sows may abort. There may be high mortality in suckling piglets, with sudden deaths from myocarditis, but no vesicular lesions. In some herds this is the first overt sign of the disease.
Sheep and goats
FMD is generally much milder in sheep and goats than in other species, and often escapes detection. Mouth lesions are not prominent.
Vesicles are most likely to occur on the dental pad and the posterior portion of the dorsal surface of the tongue. They tend to be small and heal rapidly.
Foot lesions are difficult to identify and most often occur along the coronary band and interdigital skin. It is often necessary to reflect the hair at the coronary band in order to visualize lesions. Lameness is often the only overt sign of FMD in a flock and must be distinguished from other causes of lameness. Foot lesions in sheep and goats are particularly prone to secondary bacterial infections, including foot rot.
As in other species, sudden deaths commonly occur in young lambs and kids as a result of cardiac lesions. The mortality rate may be as high as 90 percent, but is more usually about 50 percent.
Apart from the lesions that may be seen by external examination of the live animal, vesicular lesions may also be seen on the rumen pillars and possibly in other epithelial sites of the forestomachs of ruminant animals. Myocardial lesions are common in young animals. Irregular grey necrotic foci may give rise to a striped appearance (the so-called "tiger heart") of myocardium/epicardium of the heart.
The histological lesions of FMD are not highly specific but in early infection appear as multilocular fluid-filled vesicles in the stratum spinosum and cells that undergo acantholysis. Myocardial hyaline degeneration characterizes fatal cases of FMD. Confirmation of diagnosis should not be based on histopathology.
DETERMINING THE AGE OF FOOT-AND-MOUTH DISEASE LESIONS
Being able to determine the age of lesions, especially when FMD is first recognized in a herd, is a useful aid to determining the approximate time of first infection, and thus in tracing back to the origin of infection. The table below gives some indicators as to the appearance of lesions at various phases of their development. It is of more value in cattle and pigs than in small ruminants, given the fact that clinical disease in sheep and goats is relatively mild.
Approximate age of lesions
Appearance of lesions
Unruptured vesicles containing some fluid, early signs of necrosis in overlying epithelium
Unruptured, fluid-filled vesicles, overlying epithelium necrotic
Vesicles ruptured, erosions present and ragged pieces of epithelium adhering to the margins of the lesions. In the earlier phase, the exposed centre of the lesion is bright red; later the redness begins to change as fibrin deposition occurs
4 days-1 week
Erosions with little epithelium attached, margins of lesions becoming "smoother" (no longer ragged) because of early healing with regrowth of epithelium at the edge of the lesion
Healing advanced with fibrous tissue formation
Circulating neutralizing antibodies develop within four to ten days of infection. Convalescent animals usually have a very long immunity to reinfection (as long as at least five years) with closely related virus of the same serotype, but remain fully susceptible to other serotypes.
The degree of protection after vaccination is greatly influenced by the antigenic relationship between the vaccine strain and the challenge strain. Vaccines provide only partial immunity against antigenic variants of the same serotype. Potent vaccines confer immunity as early as four days after injection. However, vaccinal immunity is not long lasting and therefore revaccination at regular intervals (e.g. 6-12 months) is required. Manufacturers of commercial FMD vaccines normally recommend a primary immunization regime of an initial dose followed within three to four weeks by a second dose of vaccine. However, in endemic situations it is more usual to give two doses at six months apart and to revaccinate thereafter at yearly intervals. A proportion of vaccinated animals, although protected against the clinical disease, may become subclinically infected after natural challenge and excrete virus. It is important to note that animals incubating the disease when vaccinated may still develop the disease, sometimes in a milder form, and that vaccinated, exposed animals may still transmit infection for 7-14 days after vaccination and exposure.
Susceptible animals exhibiting excess salivation, lameness and other suggestive clinical signs should be examined carefully for vesicular lesions. If these are found, FMD should be strongly suspected and appropriate action taken immediately to secure a definitive diagnosis and prevent any further spread of the disease while this is being done. This action includes collecting appropriate diagnostic specimens (or calling for a visit to be made by a specialist diagnostic team), notifying the provincial veterinary officer (PVO) and/or chief veterinary officer (CVO), and implementing or advising on immediate quarantine measures. Personal disinfection should be carried out after inspecting suspect animals and in no circumstances should another farm be visited on the same day.
FMD can be clinically indistinguishable from other vesicular viral diseases of livestock, namely:
swine vesicular disease (which occurs only in pigs)
vesicular exanthema (which occurs only in pigs)
vesicular stomatitis (which occurs in cattle, horses and pigs).
These vesicular diseases are fairly distinctive if animals are seen in the early acute clinical stage when there are unruptured or freshly ruptured vesicles. However, there have been incidents in several countries in which vesicular lesions have been observed on the snouts and/or feet of pigs, for which the aetiology could not be determined, despite thorough virological investigations. A number of other viral diseases can be confused with the viral vesicular diseases, particularly during the later more advanced clinical stages. These include:
bovine papular stomatitis
mucosal disease/bovine viral diarrhoea
infectious bovine rhinotracheitis
peste des petits ruminants
Although mouth and muzzle lesions in these diseases are not vesicular, they could be confused with older lesions of FMD. Of the above diseases, foot lesions occur only in bluetongue and mucosal disease. Other diseases that may also be confused with the viral vesicular diseases are:
Dermatophilus and other types of mycotic stomatitis
phototoxic dermatitis with vesicle formation from contact with the leaves of plants of the family Umbelliferae (parsnips, parsley and celery)
chemical irritants and scalding
traumatic lesions of the mouth or feet
Foot lesions of FMD may be complicated by secondary bacterial infections that can mask the underlying cause. When herds or flocks are being investigated for vesicular diseases, it may be necessary to wash the feet of the animals carefully so they are free from mud and other debris before they are examined. Infected feet are often excessively warm. It is often necessary to reflect the hair at the coronary band to reveal small lesions in sheep.
The heart lesions of encephalomyocarditis (EMC) virus infection in pigs may also be confused with those of FMD in piglets.
If there are sudden deaths in young ruminant animals, Rift Valley fever, enterotoxaemia and bluetongue should be considered in the differential diagnosis.
Laboratory confirmation of a presumptive diagnosis of FMD depends upon isolation of the virus, detection of viral antigen or detection of antibodies (as long as the antibodies can be demonstrated to result from infection rather than vaccination). Detailed instructions for laboratory diagnostic procedures for FMD are to be found in the Manual of standards for diagnostic tests and vaccines (OIE, 2000). The following is a summary, with emphasis on tests that are usually used.
Collection and transport of diagnostic specimens. The preferred sample for virus isolation/antigen detection is epithelium (at least 1-2 cm square) from unruptured or freshly ruptured vesicles. Vesicular fluid should be added if available. Samples should be collected into a transport medium consisting of equal amounts of phosphate buffer and glycerol at pH 7.2-7.6 (with added antibiotics). The special containers, and advice for dispatch should be sought first.
Laboratory diagnosis should only be attempted by trained personnel in well-equipped laboratories that have adequate biosecurity.
Virus isolation. The FMD virus is best isolated in primary cell cultures of bovine thyroid or pig, calf or lamb kidney. Established cell lines such as BHK-21 and IBRS-2 may also be used, but are less sensitive. The virus may also be isolated by inoculation of tissue suspension in unweaned mice.
Negative results can only be reported after two passages of the sample in tissue culture. This may take up to four days. It is therefore extremely important to obtain the best possible quality of lesion material for dispatch to the laboratory.
Antigen detection. The two most commonly used tests are:
the complement fixation test (CFT); and
ELISA (an indirect sandwich test).
ELISA has largely replaced the CFT. The latter is sensitive and easier to apply but, as with all tests, needs to be properly standardized to optimize its sensitivity and specificity.
Antibody detection. Serological tests for FMD include:
the virus neutralization test (VNT): this is a sensitive serotype- specific test, which requires three days to provide a result;
the ELISA test (liquid or solid phase blocking): this is another sensitive serotype-specific test. It is now widely used because it provides fast results and does not require elaborate tissue-culture laboratory facilities as does the VNT. Positive results can be obtained within five hours of the laboratory receiving the sample;
ELISA tests to detect antibodies against FMD non-structural proteins (NSP): the preparation of modern FMD vaccines results in the depletion of NSP. Sera from vaccinated animals contain antibodies against structural proteins, but not against NSP such as 3ABC or 2C. ELISA tests for NSP antibodies are major FMD diagnostic advances as they allow antibody titres that result from FMD infection to be discriminated from those resulting from vaccination.
Both the VNT and ELISA are OIE-prescribed tests for international trade.
Detection of viral genetic material. Reverse transcriptase (RT) polymerase chain reaction (PCR) tests are available for FMD. PCR is a highly sensitive and specific technique but, because of the possibility of cross-contamination, as well as expense, its use is practically confined to laboratories with a considerable degree of sophistication that have this capacity for other diseases.
Tests under development. Additional diagnostic tests are under development and validation. These include pen-side tests for the detection of the FMD virus and antibody and the application of automated, mobile equipment for the rapid application of the RT-PCR test.