Foot-and-mouth disease is one of the world's most economically important viral diseases of livestock. The virus infects cattle, pigs, and sheep and many cloven-hoofed wildlife species. The infection results in vesicular lesions in and around the mouth and on the feet, resulting in the reluctance of an animal to eat or move. Confirmation of the infection requires laboratory analysis, usually involving real time RT-PCR, and serotyping is achieved using antigen ELISA. Inactivated virus vaccines are available.
Foot-and-mouth disease (FMD) is a highly transmissible disease caused by infection with an Aphthovirus, a member of the family Picornaviridae. There are 7 serotypes of the virus, termed: A, O, C, Asia 1, and SAT (Southern African Territories) 1, 2, and 3. Further diversity is found between strains within each serotype. The virus primarily affects cloven-hoofed animals of the order Artiodactyla. Livestock hosts include cattle, pigs, sheep, and goats. FMD virus has also been reported to affect >70 species of wild artiodactyls, including African buffalo, bison, giraffes, camels, and several species of deer and antelope.
Courtesy of Dr. Antonello Di Nardo, Vesicular Disease Reference Laboratory, The Pirbright Institute.
FMD is characterized by fever and vesicles in the mouth and on the muzzle, teats, and feet of animals and is spread through contact with infected animals or their excretions. The virus can also be transmitted as an aerosol via respiratory secretions and through milk, semen, and ingestion of feed from infected animals (meat and offal). In a susceptible population, morbidity can reach 100% but with rare fatalities except in young animals. FMD is distributed worldwide but has been eradicated from some regions, including North America and Europe. In endemic countries (including much of Africa, the Middle East, and southern Asia (see figure), FMD places economic constraints on the international livestock trade and can be easily reintroduced into disease-free areas unless strict precautions are in place. Outbreaks can severely disrupt livestock production and require significant resources to control, as in the 2001 UK outbreak. This outbreak, which lasted for approximately 8 months, is estimated to have cost about USD 10 billion. In nonendemic countries, a major part of the cost of outbreaks is because of lost trade and the large numbers of animals culled to limit spread of the disease, not direct effects of the disease on infected animals' performance.
Epidemiology and Transmission of Foot-and-Mouth Disease in Animals
The different virus serotypes of foot-and-mouth disease are not uniformly distributed within the endemic regions. Serotype O FMDV is responsible for approximately 70% of outbreaks globally. Six of the 7 serotypes have occurred in Africa (O, A, C, SAT-1, SAT-2, SAT-3), 4 in Asia (O, A, C, Asia-1), and 3 in South America (O, A, C). North and Central America, Australia, New Zealand, Greenland, Iceland, and Europe are now normally free of FMD (the last outbreak in Europe was in Bulgaria in 2011). There have been no reports of disease caused by serotype C FMDV anywhere since 2004, and it may now be eradicated outside of the laboratory. However, vaccination against this serotype still occurs in some places, so the complete absence of the virus in the field is difficult to prove.
The FMD virus is transmitted via direct contact with infected animals or indirect contact with secretions or excretions (including semen and milk) from infected animals or by mechanical vectors (people, horses, dogs, cats, birds, vehicles) or air movement over land or water. The virus can enter the host via inhalation, ingestion, or through skin wounds and mucous membranes. Breeding is a possible route of transmission for the SAT viruses in African buffalo populations.
A potential scenario for introduction of the virus into a previously FMD-free area is for a susceptible population, such as pigs, to be given imported food derived from an infected animal (meat or offal). Virus then spreads from pigs, which can expire up to 3,000 times more virus than cattle, to more susceptible cattle hosts via aerosol. Virus was reported to travel over water >250 km (~150 miles) from Brittany, France, to the Isle of Wight, UK, in 1981, but it usually travels no more than 10 km (~6 miles) over land. FMD has high agroterrorism potential because of its infectivity, high transmissibility through wind and by fomites, and the potential to cause enormous economic losses.
People can act as mechanical vectors of FMD by carrying virus on clothing or skin. However, FMD is not considered a public health problem.
FMD virus is environmentally resistant but can be easily inactivated outside the pH range 6–9 and by desiccation and at temperatures >56°C. It is resistant to lipid solvents such as ether and chloroform, but sodium hydroxide (lye), sodium carbonate (soda ash), citric acid, and acetic acid (vinegar) are effective disinfectants. Iodophors, quaternary ammonium compounds, hypochlorite, and phenols are less effective disinfectants, especially in the presence of organic matter.
FMD virus is shed into milk in dairy cows before clinical signs develop, so there is opportunity for virus to spread from farm to farm and from cow to calf via raw milk. FMD virus may survive pasteurization depending on the method (high temperature short time, ultra high temperature, laboratory pasteurization); the lipid component of milk protects virus during heating. FMD virus can survive for up to 20 weeks on hay or straw bedding, in dry fecal matter for up to 14 days in summer, in fecal slurry for up to 6 months in winter, in urine for 39 days, and in soil for 3 (summer) to 28 (winter) days. However, the extent of virus survival in these materials is dependent on the initial level of contamination.
Properties of Foot-and-Mouth Disease Virus in Animals
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
Foot-and-mouth disease virus, like other picornaviruses, has a positive-sense RNA genome. The RNA sequence is about 8,500 nucleotides in length and includes a single, large, open reading frame (ORF) that encodes a large polyprotein (~2,330 amino acids in length). During, and after, the synthesis of this polyprotein, it is processed, largely by virus-encoded proteases, to generate 15 mature proteins. The structural proteins of the virus (termed VP1, VP2, VP3, and VP4) are produced from the capsid precursor P1-2A (see figure Foot-and-Mouth Disease RNA Genome). The near spherical virus particle (~25–30 nm in diameter) includes 60 copies of each of the structural proteins plus a single copy of the virus genome. The proteins VP1, VP2, and VP3 are exposed on the outside surface of the virus, whereas VP4 is entirely internal.
The virus capsid serves to protect the RNA genome while it is outside of a host cell and also facilitates entry into cells by binding to specific receptors on the cell surface. After virus internalization, the RNA genome is released into the cytoplasm of the cell. It is translated, to make the viral proteins, including various nonstructural proteins, and then the RNA genome is replicated (via a negative sense RNA copy) using some of these nonstructural proteins. Packaging of the positive sense RNA by the capsid proteins generates new virus particles. Many thousands of new virus particles may be produced within an infected cell within a few hours.
Pathogenesis of Foot-and-Mouth Disease in Animals
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
The primary site of infection and replication of FMD virus is in the mucosa of the pharynx. The virus may also enter through skin lesions or the GI tract. Once distributed throughout the lymphatic system, the virus replicates in the epithelium of the mouth, muzzle, teats, feet, and areas of damaged skin (eg, knees and hocks of pigs). Vesicles then develop and rupture within 48 hours. More than 50% of ruminants that recover from the disease and also those that are vaccinated and have then been exposed to the virus can become carriers, ie, they have a low level of infectious virus in their pharyngeal region. The carrier state can last for up to 3.5 years in cattle, 9 months in sheep, and >5 years in African buffalo. Strikingly, such persistent infections do not occur in pigs. The risk posed by these carrier animals seems low (but not zero) because it has not been possible to transmit the disease (under controlled conditions) from carrier cattle to naive cattle by close contact for extended periods of time. However, transmission of the disease has been achieved from carrier buffalo to cattle and also by direct transfer of pharyngeal fluid from carrier cattle to naive cattle.
The incubation period of FMD is variable and depends on the host, environment, route of exposure, and virus strain. After infection with FMD virus, the average incubation period for sheep and goats is 3–8 days, ≥2 days for pigs, and 2–14 days in cattle. The incubation period can be as short as 18 hours for host-adapted strains in pigs, especially under intense direct contact. It is important to be aware that animals can transmit the virus before the appearance of clinical signs because animals have virus in the pharynx and in the blood before disease is observed.
Clinical Findings of Foot-and-Mouth Disease in Animals
Clinical signs in cattle include fever of ~40°C, followed by vesicular lesion development on the tongue, hard palate, dental pad, lips, gums, muzzle, coronary band, interdigital cleft, and teats in lactating cows. Acutely affected individuals may salivate profusely (drooling), stamp their feet, and prefer to lie down. Ruptured oral vesicles can coalesce and form erosions but heal rapidly, roughly 11 days after vesicle formation. Vesicles on the feet take longer to heal and are susceptible to bacterial infection leading to chronic lameness. Secondary bacterial mastitis is common due to infected teat vesicles resulting in resistance to milking. After vesicular disease develops, cattle quickly lose condition and milk yield diminishes, which can persist chronically. Occasionally, young calves may die without prior clinical signs of illness because of virus-induced damage to the developing myocardium.
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
Courtesy of National Veterinary Institute, DTU Vet, Lindholm, Denmark.
Infected pigs show mild lameness and blanching around the coronary band and may develop a fever of up to 41.5 °C. Affected pigs become lethargic, huddle among other pigs, and have little interest in feed. Vesicles develop on the coronary band and the heel of the foot including accessory digits, snout, mandible, and tongue. Additional vesicles may form on the hocks and knees of pigs housed on rough surfaces. Depending on the severity of vesicles, the horn of the foot may completely slough off and cause chronic lameness in recovered pigs. Young pigs, < 14 weeks old, may die without clinical signs of illness because of virus-induced myocarditis; this is more frequent in pigs than in calves.
Clinical signs of FMD in sheep and goats can be largely inapparent. However, lameness is usually the first clinical sign of FMD infection observed in sheep and goats. This is followed by fever and vesicular development on the interdigital cleft, heel bulbs, coronary band, and mouth. Vesicles may also form on the teats of lactating animals and rarely on the vulva and prepuce. Secondary infections result in reduced milk yield, chronic lameness, and predisposition to other viral infections, including sheep/goat pox and peste des petits ruminants. Similarly to young pigs, infection in immature sheep and goats can result in death without clinical signs due to heart failure.
Experimentally infected camelids are commonly reported to have mild clinical illness, if at all, but can have severe infections resulting in salivation and mouth lesions and sloughing of the footpad and skin of the tarsal and carpal joints. Water buffalo can have mouth and foot lesions, which heal faster and are less severe than those in cattle. FMD infections in wildlife resemble clinical illness in their domestic counterparts, but more severe lesions such as sloughing of antlers or toe horn are reported.
Aging of lesions is an important part of epidemiologic investigation of an FMD outbreak. Government agencies and professional societies have produced brochures that can help practitioners estimate the age of clinical lesions of FMD. These are freely available online from groups in both the USA and Europe.
Diagnosis of Foot-and-Mouth Disease in Animals
RT-PCR assay, serology, or virus isolation
In cattle and pigs, the clinical signs of FMD are indistinguishable from those of vesicular stomatitis, and in pigs from those of swine vesicular disease , vesicular exanthema and infection by Seneca Valley virus. Therefore, laboratory confirmation is essential for diagnosis of FMD and should be performed in specialized laboratories that meet OIE requirements for Containment Group 4 pathogens. Countries lacking access to a national or regional laboratory meeting these guidelines should send specimens to an OIE FMD reference laboratory.
The tissue of choice for sampling is vesicular epithelium or fluid. At least 1 g of epithelium should be placed in a transport medium of phosphate-buffered saline (PBS) or equal parts glycerol and phosphate buffer with pH 7.2–7.6. Samples should be kept refrigerated or transported on ice. If vesicles are not present, oropharyngeal fluid can be collected via probang cup or pharyngeal swabbing for virus isolation or reverse transcription PCR (RT-PCR) assay. Serum (blood) samples may also be tested by these means (OIE Terrestrial Animal Health Code 2019), but viremia is fairly short lived (a few days); thus, when lesions are healing the virus has been cleared from the blood and antibodies can be detected. Repeated sampling of oropharyngeal fluid may be necessary to identify a carrier, because virus presence in such animals is low and fluctuates.
Laboratory diagnosis is usually performed by real time RT-PCR assay; two separate assays targeting two different regions of the RNA genome are commonly used. These assays are very sensitive and can detect FMDV genomes even in poorly stored samples when virus infectivity has been lost. The presence of virus can also be demonstrated using antigen ELISAs, and this can determine the serotype. This is the preferred method for countries with endemic FMD for virus detection and serotyping (OIE Terrestrial Animal Health Code 2019). In reference laboratories, sequencing of part of the genome (encoding the capsid proteins) is frequently performed to determine the serotype and lineage of the strain. Concurrent virus isolation may be performed in appropriate cell culture systems. Commercially available lateral flow devices for rapid detection of virus antigen at the pen-side have proven useful.
Serologic tests for FMD are used to certify animals for import/export (ie, trade), to confirm suspected cases of FMD, test efficacy of vaccination, and provide evidence for absence of infection. Testing cut-offs may be set at different levels for herd-based surveillance versus certifying freedom of infection for trade purposes. The choice of serologic test depends on the vaccination status of the animals. Serologic tests for antibodies to the structural (capsid) proteins of the virus are not informative in vaccinated animals, because FMD vaccines induce antibodies to these proteins. However, detection of antibodies to the nonstructural proteins, which are produced only during virus replication, can be used to determine past or present infection with any of the 7 serotypes, whether or not the animal has been vaccinated. However, they are less sensitive and may result in false-negatives in cases with limited virus replication, such as vaccinated animals that become infected, because the vaccine suppresses viral replication (OIE Terrestrial Animal Health Code 2019).
Treatment, Control, and Prevention of Foot-and-Mouth Disease in Animals
In regions that are normally FMD-free, control of the disease is typically attempted by culling all animals on infected premises, and animal movement controls are imposed to reduce the risk of virus spread
In both normally FMD-free regions and endemic areas, vaccination around outbreaks may be used to limit the spread of the disease
No treatments for infected animals are available
The OIE classifies countries and regions as: FMD-free without vaccination; FMD-free with vaccination; suspended FMD-free status with or without vaccination; and unrecognized (OIE Terrestrial Animal Health Code, 2019).
The current global status of FMD distribution shows geographic areas where FMD prevalence has been high over long periods of time. They are commonly located in economically challenged countries where veterinary services and resources are inadequate to control or eradicate FMD.
Combined use of trade and movement restrictions of animals and animal products has not completely prevented introductions of FMD into FMD-free areas. These virus incursions into countries or regions where FMD is not enzootic are usually controlled by culling of all infected and susceptible animals in infected herds, strict restriction of animal and vehicle movement around infected premises, proper carcass disposal, and environmental disinfection, without the use of vaccines.
Inactivated virus vaccines protect for only 4–6 months against the specific serotype(s) contained in the vaccine. Billions of doses are used each year and protect animals from clinical illness but not viral persistence in the pharyngeal region, and thus vaccinated animals can be carriers of infectious virus. Additionally, it is difficult to distinguish infected animals from vaccinated animals unless purified vaccines are used. Therefore, vaccination is used more in enzootic countries to protect production animals, particularly high-yielding dairy cattle, from clinical illness because slaughter of all at-risk individuals may be economically unfeasible and can cause food shortages.
Rapid disease reporting is essential to control an FMD outbreak in nonendemic countries. During an outbreak, tracing is done through epidemiologic inquiries to help identify the source of disease introduction. Sequencing of viruses can also identify the source of closely related viruses. When mass culling is performed, infected carcasses must be disposed of via incineration, burial, or rendering on or close to the infected premises. Scavengers and rodents should be prevented or killed to prevent mechanical dissemination of virus. Buildings should be cleaned with a mild acid or alkaline disinfectant and fumigation, and people that have come into contact with virus must decontaminate their clothing and avoid contact with susceptible animals for a period of time.
In some regions, FMD persistence in wildlife populations, such as the wild African buffalo, can make the prospect of FMD eradication very difficult. Control measures, such as fencing of wildlife reserves to prevent contact with domestic livestock, have helped limit the spread of virus in certain areas. A twice-yearly vaccination buffer zone in livestock near endemic wildlife reserves may additionally help reduce outbreaks. A progressive control pathway (PCP) has been developed by FAO and adopted by OIE to enable countries to improve their own FMD control so that the global disease situation will improve.
There is no specific treatment for FMD, but supportive care may be allowed in countries where FMD is endemic.
Key Points
Control of FMD can be successfully achieved with good veterinary services, enabling rapid diagnosis and implementation of control measures, including, in some circumstances, the use of vaccines.
In countries that are normally FMD-free, culling of infected animals and those at high risk of getting infected is undertaken. However, public concern about mass culling has encouraged the search for improved vaccines against the disease.
Current vaccines have a variety of limitations and require the production of large quantities of infectious virus prior to its inactivation. This must be performed in expensive, high-containment facilities.
