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Overview of Foot-and-Mouth Disease


Foot-and-mouth disease (FMD) is a highly infectious viral disease of cloven-hoofed species characterized by fever and vesicles in the mouth and on the muzzle, teats, and feet. In a susceptible population, morbidity approaches 100%. The disease is rarely fatal except in young animals.

Cattle are the most susceptible. Domestic pigs are important hosts and are very effective in propagating the disease. In sheep and goats, the clinical manifestations of infection are usually less severe than in cattle and pigs. All species of deer and antelope, Indian elephant, and giraffe are susceptible to FMD, but Old World camels are resistant to natural infection. In Africa, Cape buffalo infection is asymptomatic. South American species such as alpacas and llamas, although susceptible, are probably of no epidemiologic significance. Rats, mice, and guinea pigs can be infected experimentally.

FMD is endemic in the Middle East, Iran, the southern countries of the former Soviet Union, India, and southeast Asia. Sporadic outbreaks occurred in South Korea in 2000 and 2002, Japan in 2000, and in peninsular Malaysia. FMD is restricted to Luzon island in the Philippines. Australasia and Indonesia are free of FMD, as are Central and North America. In South America, Chile, southern Argentina, Guyana, Surinam, and the region of Colombia bordering Panama are free; large outbreaks of FMD in Uruguay and central Argentina during 2001 were brought under control, and these areas together with Paraguay and large parts of Brazil are now considered free areas in which vaccination is still used. Most of sub-Saharan Africa has endemic FMD, and also Egypt, Ethiopia, and Eritrea; FMD has returned to Zimbabwe associated with economic and social changes, and sporadic outbreaks have also occurred in the previously FMD-free zones of South Africa, Namibia, and Botswana.

In Europe, an outbreak in Greece on the border with Turkey in 2000 was quickly eliminated, but in 2001, FMD was introduced into the UK, from where it spread to the Republic of Ireland, the Netherlands, and France. The strain causing the outbreak was the same as that found throughout Asia, and was eventually brought under control in the UK following the slaughter of >4 million animals, without the use of vaccination. Vaccination was used in the Netherlands, and all vaccinated animals were subsequently slaughtered.

FMD is caused by an aphthovirus of the family Picornaviridae. There are 7 immunologically distinct serotypes: A, O, C, Asia 1, and SAT (Southern African Territories) 1, 2, and 3. Within each serotype, there are a large number of strains that exhibit a spectrum of antigenic characteristics; therefore, more than one vaccine strain for each serotype, particularly O and A, is required to cover the antigenic diversity. Strains are characterized by their genomic relationships and their antigenic similarities with established vaccine strains. (Previous classification into subtypes became untenable as the number of subtypes rapidly increased.) The development of nucleotide sequence analysis has enabled the definition of topotypes, based on the capsid protein genes. For example, FMD virus type O can be divided into 8 topotypes, each containing viruses that differ in VP1 gene sequence by at least 15% and are also geographically distinct.

The virus is quickly inactivated outside the pH range of 6.0–9.0 and by desiccation and temperatures >56°C, although residual virus may survive a considerable time when associated with animal protein (for instance, a proportion of FMD virus in infected milk will survive pasteurization at 72°C for 15 sec). FMD virus is resistant to lipid solvents such as ether and chloroform. Because of the sensitivity of the virus to acid and alkaline pH, sodium hydroxide, sodium carbonate, and citric or acetic acid are effective disinfectants.

Transmission of FMD is generally by contact between susceptible and infected animals. Infected animals have a large amount of aerosolized virus in their exhaled air, which can infect other animals via the respiratory or oral routes. All excretions and secretions from the infected animal contain virus, and virus may be present in milk and semen for up to 4 days before clinical signs appear. Aerosolized FMD virus can spread a considerable distance as a plume, depending on weather conditions, particularly when the relative humidity is >60% and when the topography of the surface over which it is dispersing does not cause turbulence. FMD has been transmitted to calves via infected milk, and milk tankers carrying infected milk have been implicated in the spread of disease between farms. Fodder can become contaminated after contact with infected animals and iatrogenic spread of FMD has been reported.

Although horses, dogs, and cats are not affected by FMD, they can act as mechanical vectors, as can humans. Also, avian species are not susceptible to infection, but they can carry virus on their feet and feathers and will excrete virus after ingesting infected material. Therefore, birds may carry the virus, although their role in dissemination is unclear.

A typical scenario for the introduction of FMD into a previously clear area is for pigs to be fed imported food derived from an infected animal (as meat, offal, or milk); virus then spreads by aerosol from the infected pigs to cattle, which are the most likely species to be infected by the respiratory route because of their large respiratory volume. FMD virus can survive in dry fecal material for 14 days in summer, in slurry up to 6 mo in winter, in urine for 39 days, and on the soil between 3 (summer) and 28 (winter) days.

Ruminants that have recovered from infection and vaccinated ruminants that have contact with live FMD virus can serve as foci of infection and carry the virus in the pharyngeal region for up to 3.5 yr in cattle, 9 mo in sheep, and ≥5 yr in African buffalo. Experimentally, it has not been possible to show transmission from a carrier bovid to an in-contact susceptible animal, but there is evidence that under field conditions these carrier animals initiate new outbreaks of disease. FMD virus can be recovered from carrier animals by culturing a sample of pharyngeal mucus and superficial cells (collected using a probang cup) on susceptible tissue culture, such as primary bovine thyroid cells. However, the technique is probably only 50% reliable in identifying a carrier using a single sample because the quantity of virus found in the pharynx varies on different occasions.

The primary site of infection and replication is usually the mucosa of the pharynx, although the virus can enter through skin abrasions or the GI tract. Virus is distributed through the lymphatic system to sites of replication in the epithelium of the mouth, muzzle, feet, and teats, and also to areas of damaged skin (eg, the knees and hocks of pigs kept on concrete). Vesicles develop at these sites and rupture, usually within 48 hr. The viremia persists for 4−5 days.

Antibody production can be detected from 3–4 days after the first clinical signs and is usually sufficient to clear the virus.

The incubation period for FMD is 2–14 days, depending on the infecting dose, susceptibility of the host, and strain of virus—in pigs, it may be as short as 18 hr with some strains of FMD virus. The clinical signs are more severe in cattle and intensively reared pigs than in sheep and goats, and FMD has frequently been ignored or misdiagnosed in small ruminants.

In cattle and pigs, after the incubation period, anorexia and fever of up to 106°F (41°C) may develop. Cattle salivate and stamp their feet as vesicles develop on the tongue, dental pad, gums, lips, and on the coronary band and interdigital cleft of the feet. Vesicles may also appear on the teats and udder, particularly of lactating cows and sows, and on areas of skin subject to pressure and trauma, such as the legs of pigs. Young calves, lambs, kids, and piglets may die before showing any vesicles because of virus-induced damage to the developing cells of the myocardium. Milk yield drops dramatically in milking animals, and all animals show a loss in condition and growth rate that may persist after recovery. Sheep and goats may develop only a few vesicles on the coronary band and in the mouth. Vesicles in the mouth, even when severe, usually heal within 7 days, although recovery of the tongue papillae takes longer. Lesions on the mammary gland and feet frequently develop secondary infections, resulting in mastitis, underrunning of the sole, and chronic lameness. In pigs, the complete horn of the toe may be lost. Cattle and deer may also lose one or both horns of the foot, and deer may shed their antlers.

In cattle and pigs, the clinical signs of FMD are indistinguishable from those of vesicular stomatitis (see Vesicular Stomatitis), and in pigs from those of swine vesicular disease (see Swine Vesicular Disease) and vesicular exanthema (see Vesicular Exanthema of Swine). Samples of vesicular epithelium or vesicular fluid should be sent in phosphate-buffered saline (pH 7.4) to the national laboratory responsible for the diagnosis of FMD, or otherwise to the OIE/FAO World Reference Laboratory for FMD, Pirbright, UK, by previous arrangement. Samples must be kept as close as possible to pH 7.4 to prevent destruction of the FMD virus and antigen. They should be securely packed in double leak-proof containers that comply with national and, when appropriate, international regulations for the shipment of pathologic and hazardous material.

Samples are prepared as a 10% suspension, inoculated onto susceptible tissue culture, and directly typed by ELISA. Isolated FMD virus is characterized by antigenic comparison with existing FMD vaccine strains, and the nucleotide sequence of a segment of the 1D gene is determined for comparison with other strains of the same serotype to identify a possible origin of the outbreak. ELISA are available to show serologic evidence of vaccination against FMD or recovery from infection: either the liquid phase blocking ELISA, or the more recently introduced solid phase competition ELISA, which is equally sensitive but more specific.

Tests for antibodies to the nonstructural proteins (NSP) of FMD virus can be used to distinguish an animal that has been infected from one that has been vaccinated, as only infected animals will have supported live replicating FMD virus, which express the NSP as part of their replication cycle. Virus in FMD vaccine is dead, and consequently there is no expression of NSP; therefore, no antibodies are formed in the host to these proteins. However, there may be sufficient NSP contamination in some vaccines to cause an antibody response, particularly to the 3D protein, in some animals that have received multiple vaccinations. Conversely, vaccinated animals that have had contact with live virus and become carriers of live FMD virus may fail to produce antibody to NSP, as the immunity provided by the vaccination suppresses viral replication.

Rapid diagnostic kits are becoming available for on-farm diagnosis, but they will require stringent validation. PCR is also becoming more frequently used for rapid diagnosis; although difficult to fully validate, this test is likely to be more widely used in the future.

The occurrence of FMD in countries previously free of the disease can have a major effect on local and international trading arrangements. Many countries free of FMD have a policy of slaughter of all affected and in-contact susceptible animals and strict restrictions on movement of animals and vehicles around infected premises. After slaughter, the carcasses are either burned or buried on or close to the premises, and the buildings are thoroughly washed and disinfected with mild acid or alkali and by fumigation. Tracing is done to identify the source of the outbreak and premises to which FMD virus could have already been transmitted by infected animals or animal products, by contaminated vehicles or people, or aerosol.

In areas or countries free of FMD in which this is not possible, control is by movement restriction, quarantine of affected premises, and vaccination around (and possibly within) the affected premises. This has the disadvantage that many carrier animals may remain after the outbreak, and quarantine may not be sufficiently long to prevent their subsequent movement.

In countries in which FMD is endemic, protection, particularly of high-yielding dairy cattle, is by a combination of vaccination and prevention of FMD virus entering the dairy premises. This can be difficult if prevalence of FMD in the unvaccinated population is high and climatic conditions are suitable for aerosol transmission.

FMD vaccine is a killed preparation and, at best, affords good protection against challenge for 4–6 mo. However, the antigenic diversity of virus strains within each of the serotypes is an additional complication, so it is necessary to ensure that vaccines contain strains antigenically similar to the potential outbreak strains. Otherwise, the duration of immunity provided by vaccines containing dissimilar strains may be very short. FMD vaccines for pigs require an oil adjuvant, whereas those for ruminants may contain an oil or aluminum hydroxide/saponin adjuvant. There are currently no recommended alternatives to vaccine antigens derived from whole virus grown in tissue culture and then chemically inactivated with an aziridine, usually binary ethyleneimine.

Last full review/revision March 2012 by Brian W. J. Mahy, BSc, MA, PhD, ScD, DSc

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