Foot-and-Mouth Disease

Agent
Hosts
Epidemiology
FMD As a Biological Weapon
Clinical Features
Differential Diagnosis
Laboratory Features
Treatment
Prevention
Outbreak Control
Public Health Issues
References

Agent

Foot-and-mouth disease (FMD) is a contagious viral disease of sheep, cattle, pigs, and wild ruminants. Key facts about the disease follow (see References: Murphy 1999):

• Girolamo Fracastor first described FMD in 1546 in regard to an epidemic in 1514 in Italy (see References: Blancou 2002).
• FMD is caused by a nonenveloped virus of the genus Aphthovirus, family Picornaviridae.
• The virus's genetic materal is a positive-sense (can act directly as messenger RNA) single-stranded RNA molecule.
• There are seven immunologically distinct serotypes: A, O, C, Asia 1, SAT (Southern African Territories) 1, SAT 2, and SAT 3.
• Numerous strains (quasispecies) have arisen within each serotype from error-prone RNA replication, confounding control and diagnosis of the disease (see References: Domingo 2002).
• Immunity to one serotype does not confer immunity to other serotypes, and vaccines must be tailored to the local strain.
• The virus replicates in the cytoplasm of host cells.
• The virus is inactivated by pH outside the range of 6 to 9 and by sodium hydroxide, sodium carbonate, and citric acid. It is resistant to iodophores, quaternary ammonium compounds, and phenols.

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Hosts

• Cloven-hoof mammals of the order Artiodactyla, including cattle, pigs, sheep, goats, buffalo, yaks, and wildlife
• Camels, llamas, and alpacas (low susceptibility and little epidemiologic significance)
• Antelope, elephants, and giraffes (susceptible)
• Rats, mice, hedgehogs, and armadillos (susceptible under experimental conditions)
• African Cape buffalo (major maintenance host for the SAT serotypes)

Source: Lubroth 2002 (see References).

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Epidemiology

Transmission

FMD virus can be transmitted through a variety of mechanisms:

• Inhalation or ingestion (from infected source to susceptible animals)
• Direct contact with infected animals
• Mechanical fomites (eg, vehicles, instruments, feed)
• Airborne (up to 60 km overland and 300 km by sea) in temperate zones under proper conditions (these include a high viral load [eg, a swine herd infection], stable atmospheric conditions, and a susceptible population downwind)

Source: Lubroth 2002(see References).

Occurrence

• FMD is enzootic in parts of Asia, South America, the Middle East, and Africa, where the disease is not widespread but occurs in sporadic zones under favorable conditions.
• A recent outbreak occurred in Europe, originating in the United Kingdom in February 2001 and spreading to France and the Netherlands (see References: Davies 2002).
• It is presumed the outbreak was caused by feeding swine swill contaminated with a virus that originated in India (Pan Asian O strain), but the exact method of entry is yet to be determined.
• The epidemic was controlled by the "stamping out" method—slaughter of affected and in-contact animals (see below).
• The last recorded case of FMD in the United Kingdom was in September 2002.
• The epidemic cost an estimated 2.7 billion British pounds (excluding lost tourism and associated revenue) and led to the slaughter of about 4 million animals on 2,000 farms.
• A natural outbreak in Taiwan in 1997 cost an estimated $378.6 million (see References: Tharratt 2002)
• Weekly updates on FMD occurrences around the world are available from the Office International des Epizooties (World Organization for Animal Health) (see References: OIE: Disease information in the last 18 months). Maps of outbreaks around the world are available from the Food and Agriculture Organization of the United Nations (see References: FAO).
• A updated list of countries that are FMD-free without vaccination is available at the World Organization for Animal Health Web site (see References: OIE: List of foot and mouth disease free countries).

Communicability

• Sheep act as maintenance hosts, pigs act as amplifiers, and cattle act as indicators.
• As demonstrated in the European outbreak, sheep are often infected and often spread the virus to susceptible animals and the environment without showing obvious clinical signs. Mild clinical signs complicated by concomitant occurrence of other common diseases such as contagious ecthyma and foot rot can mask the lesions, allowing for diffuse dissemination of FMD (see References: Hughes 2002).
• When the disease spreads to pigs, it infects the whole herd very rapidly. After becoming infected, pigs produce 1,000 times more virus particles in their respiratory secretions than cattle do. The high level of virus shedding increases the opportunity for aerosol spread and environmental contamination.
• Often the disease is first recognized in cattle because the lesions develop sooner in the course of the disease in cattle and manifest with more severe clinical signs.
• Virus is shed in saliva, feces, urine, milk, semen, and breath for up to 4 days before clinical signs appear in acutely infected animals.
• The virus can remain viable on a variety of materials for variable lengths of time, depending on environmental conditions (survival decreases with increasing heat and decreasing humidity) (see References: Bartley 2002):
• Fecal material: Up to 100 days (liquid slurry)
• Hay: Up to 105 days
• Bran: Up to 140 days
• Wool: Less than 21 days, average 18 days
• Snow-covered soil: More than 185 days
• Meat and byproducts in which pH remains above 6 can serve as a source of viable virus.
• Animals that have recovered or have been vaccinated can become carriers. Animals with virus persistence in the pharyngeal region more than 28 days post infection are considered carriers. Different animals can be carriers for different lengths of time (see References: Barnett 2002):
• Cattle: Up to 3.5 years
• Sheep: Up to 9 months
• African Cape buffalo: Lifelong (herd setting)
• Pigs: Do not become carriers

Source: House 1998, Davies 2002 (see References).

FMD As a Biological Weapon

FMD is of concern as a biological weapon for the following reasons:

• The disease causes a high rate of morbidity in multiple species.
• The disease is highly communicable and spreads rapidly once introduced into nonimmune herds. It is defined by the OIE as a category A disease: "Communicable diseases which have potential for serious and rapid spread, irrespective of national borders, which are of serious socioeconomic or public health consequence and which are of major importance in the international trade of livestock and products" (see References: OIE: OIE classification of diseases).
• State public health officials and state veterinarians agreed in a 2001 survey that the risk of a bioterrorism attack with an agent affecting animals was greater than the risk of an attack with an agent affecting people. Both groups shared similar risk assessments of FMD as a bioterrorism agent (see References: Tharratt 2002).
• FMD can lead to dramatic economic losses (see References: Paarlberg 2002):
• Up to $14 billion (9.5%) of US farm income would be lost in the event of an outbreak similar to the 2001 epidemic in the UK, according to recent economic models.
• The most affected sectors would be the cattle, milk, sheep, and swine markets.
• This model predicted that most loss would not be from decreases in production but rather from lost export markets and decreases in consumer demand. Without adverse consumer reaction, the losses would be closer to $6.8 billion.

Clinical Features

The clinical features of FMD are outlined in the table below (see References: OIE: Foot-and-mouth disease; Remond 2002).

Clinical Features of FMD
Feature	Characteristics
CLOVEN HOOFED MAMMALS*
Incubation period†	2-14 days
Clinical signs	—Initial sign is pyrexia (up to 106°F 1-2 days before other clinical signs) —Pyrexia is followed by anorexia, agalactia in milking animals, and appearance of vesicles —Vesicles in oral cavity are on mucosal surfaces, including tongue, dental pad, gums, and lips —Vesicles on feet are on bulbs of heel, interdigital cleft, and coronary bands —Other sites for vesicles include muzzle, nares, and teats —Painful lesions cause profuse drooling, bruxism, foot stamping, and lip smacking —Rupture of vesicles occurs within hours to 2 days, leaving erosions —Recovery generally occurs within 8-15 days
Complications	—Tongue erosions, further increasing anorexia —Superinfection of lesion, particularly on feet —Hoof deformation or sloughing of hoof horn —Mastitis with permanent impairment of milk production —Myocarditis —Abortion —Permanent weight loss, loss of heat control ("panters") due to pituitary effects
Case-fatality rate	—Greater than 60% in young animals of all susceptible species —Death in young animals primarily due to myocardial effects
SHEEP AND GOATS‡
Incubation period†	2-14 days
Clinical signs in addition to those above	—Lesions less pronounced than in other species —Foot lesions may go unrecognized —Lesions in sheep most visible in dental pad
PIGS
Incubation period†	2-14 days
Clinical signs in addition to those above	—Vesicles most commonly seen on rostrum of snout and around nares —Vesicles also can appear on tongue, dental pad, gums, cheek, hard and soft palate, lips, muzzle, coronary bands, teats, udder, corium of dewclaws, and interdigital spaces —Erosive lesions also can be seen in areas of surface contact, such as the hocks and tarsal areas (see Figure from Merck Veterinary Manual [see References: Kitching 1998])
*Visible lesions and clinical signs in cattle typically develop sooner and are more severe than in sheep, pigs, and goats. †Incubation period depends on the infective dose, host susceptibility, and viral strain. ‡Owing to mild signs in sheep, diagnosis may be delayed and virus may spread to other animals and to environment during that period.

Differential Diagnosis

The following three diseases are clinically indistinguishable so require laboratory diagnosis:

• Vesicular stomatitis: Vesicular stomatitis virus, family Rhabdoviridae
• Swine vesicular disease: Swine vesicular disease virus, family Picornaviridae
• Vesicular exanthema of swine: Vesicular exanthema of swine virus, family Caliciviridae

Other conditions to consider in differential diagnosis:

• Rinderpest: Rinderpest virus, family Paramyoviridae
• Infectious bovine rhinotracheitis: Bovine herpesvirus 1, family Herpesviridae
• Bluetongue: Bluetongue virus 1-25, family Reoviridae
• Bovine herpes mammillitis: Bovine herpesvirus 2, family Herpesviridae
• Bovine papular stomatitis: Bovine papular stomatitis virus, family Poxviridae

• Malignant catarrhal fever: Alcelaphine herpes virus 1, family Herpesviridae
• Peste des petits ruminants: Peste des petits ruminants virus, family Paramyoviridae
• Bovine viral diarrhea: Bovine viral diarrhea virus, family Flaviviridae
• Bovine mucosal disease: Occurs in cattle persistently infected with bovine viral diarrhea virus
• Foreign bodies or trauma

Source: Lubroth 2002 (see References).

Laboratory Features

The World Organization for Animal Health–prescribed tests for trade purposes are the enzyme-linked immunosorbent assay (ELISA) and virus neutralization,with complement fixation as the alternative text, as descibed in the Manuel of Standards for Diagnostic Tests and Vaccines (see References: OIE: Foot-and-mouth disease).

Virus Isolation

Virus isolation can be used to diagnose FMD, but owing to the high level of biosecurity needed and the time required for this method, it has largely been replaced by other methods.

• Cells such as bovine thyroid, swine bovine, or ovine kidney cells as well as suckling mice can be used for isolation.

Antigen Detection Methods

Positive diagnosis is based on demonstration of the FMD antigen in clinical specimens.

• Complement fixation and virus neutralization have largely been replaced by antigen-capture ELISA (see References: Domingo 2002).
• Virus neutralization tests depend on tissue cultures and are therefore more prone to variability than ELISAs.
• ELISA uses monoclonal antibodies or serotype-specific serum.
• ELISA is more specific and sensitive and is not affected by pro- and anti-complement factors.

Antibody Detection Methods

Positive diagnosis can be based on demonstration of specific antibody titers in nonvaccinated animals in which vesicular lesions are present (see References: Remond 2002)

• ELISA methods or virus neutralization can be employed as serotype-specific serologic tests.
• Virus neutralization results can take 2 to 3 days, and false-positives (low titer) can occur in severely diseased animals.
• The ELISA test is faster, has less variability, and requires less restrictive biocontainment facilities.
• ELISA testing can be performed on milk in surveillance situations.
• Nonserotype-specific ELISA tests for antibodies to nonstructural proteins are available. They have a lowered sensitivity and lack standarization but can be employed for herd screening in an outbreak (see References: Toma 2002).

Other Diagnostic Methods

• Reverse transcriptase polymerase chain reaction (rt-PCR) and in-situ hybridization are being developed as diagnostic methods (see References: Remond 2002).

• A portable "pen side" rt-PCR test has been evaluated in a limited number of trials with favorable results (100% specificity, sensitivity equal to or exceding virus isolation standard) as a rapid, sensitive test for FMD. It also poses an advantage of detection prior to clinical signs but has yet to be field tested and validated (see References: Callahan 2002, Reid 2002).

Specimen Collection

Samples should be packaged and shipped according to national and international hazardous material shipping requirements, and laboratories should be notified when specimens are being submitted (see References: OIE: Foot-and-mouth disease).

Specimen collection and submission for foot-and-mouth disease diagnosis
Tissue Type	Transport Considerations
Epithelium	—1 g epithelium with intact vesicles or recently ruptured vesicles in transport media —Transport media containing 1:1 glycerol, 0.04 M phosphate buffer (pH 7.2-7.4) with antibiotics (1,000 IU penicillin) —Phosphate buffer solution can be substituted for phosphate buffer if final pH is 7.2-7.4 —Samples should be refrigerated, not frozen, until arrival at laboratory
Oropharyngeal fluid	—Collected by probang cup (speculum) or swab in transport media —Transport media containing 0.08 M phosphate buffer with 0.01% bovine albumin, 0.0002% phenol red, and antibiotics (1,000 IU penicillin) and a final pH of 7.2 —Samples should be immediately frozen to –40°C and transported on solid carbon dioxide or liquid nitrogen until arrival at laboratory

Treatment

There is no specific treatment for animals affected with FMD (see References: Kitching 1998).

Prevention

• Protect FMD-free areas by animal movement control and surveillance.
• Quarantine infected animals and place import restrictions on feed, animal products, and livestock from areas without FMD-free status.
• Give routine vaccinations in enzoonotic (non-FMD-free) regions to reduce production impact of the disease.

Source: Kitching 1998 (see References).

Outbreak Control

Outbreaks can be controlled by one or a combination of two methods: Stamping out (slaughter of all animals) and routine vaccination of host animals (see References: OIE: Foot-and-mouth disease; Domingo 2002).

Stamping-out procedures

• Quarantine of the premises
• Slaughter of affected, recovered, and exposed animals
• Trace-back to the source of infection and other potential exposures
• Movement restriction around affected premises
• Disinfection of premises and all infected materials with sodium hydroxide, sodium carbonate, or citric acid
• Destruction of carcasses, manure, and animal products in the area (usually by incineration)
• 21-day movement and restocking restrictions of the premises

Vaccination in Conjunction with Slaughter

• Ring vaccination, possibly within the infected premise, can be employed to control the spread of disease. This method was used in the Netherlands during the FMD outbreak in 2001 (see References: Barnett 2002).
• In areas densely populated with livestock and with particular regard to pigs, ring vaccination poses a valuable tool to deal economically with an outbreak that is recognized early. In areas sparsely populated with livestock, stamping out or "ring culling" is the economically optimal method for dealing with an outbreak (see References: Tomassen 2002).

Routine Vaccination

• Conventional vaccines are typically inactivated virus with an adjuvant. Immunity lasts 4 to 6 months after two initial vaccinations 1 month apart, depending on the antigenic relationship between the vaccine and the outbreak strains (see References: Toma 2002).
• Protection is conferred a minimum of 4 days after vaccination in cattle and 21 days in pigs. Protection is considered to be the prevention of clinical signs and therefore of the associated viral shedding.
• The currently employed vaccine approach has the potential to produce carrier status in recipient animals. Research is currently under way to produce a marked vaccine using newer molecular techniques (see References: Domingo 2002).
• Many countries have an antigen banking arrangement, where FMD antigens are stored on liquid nitrogen, ready to be manufactured into vaccine in an emergency (see References: Barnett 2002).

• If vaccines are used in a previously FMD-free area, recovery of disease-free status occurs after 12 months of no reported cases without slaughter of vaccinated animals. Recovery of status can be attained after 3 months of no reported cases if the vaccinated animals are slaughtered along with affected and contact animals (see References: Toma 2002).

Public Health Issues

• FMD is not considered a public health threat, although humans can contract the disease. FMD virus can cause pyrexia, anorexia, and vesicular lesions in humans. Most reported cases in humans have been in laboratory workers and in people having close contact with affected animals (see References: David 2001, Lubroth 2002).
• FMD should not be confused with hand, foot, and mouth disease, which does affect humans.

References

Barnett P, Garland AJ, Kitching RP, et al. Aspects of emergency vaccination against foot-and-mouth disease. Comp Immunol Microbiol Infect Dis 2002;25(5-6):345-64 [Abstract]

Bartley LM, Donnelly CA, Anderson RM, Review of foot-and-mouth disease virus survival in animal excretions and on fomites. Vet Rec 2002 Nov 30;151(22):667-9

Blancou J. History of control of foot and mouth disease. Comp Immunol Microbiol Infect Dis 2002;25(5-6):283-96 [Abstract]

Callahan JD, Brown F, Osorio F. Use of portable real-time reverse transcriptase polymerase chain reaction assay for rapid detection of foot-and-mouth disease virus. J Am Vet Med Assoc 2002 Jun 1;220(11):1636-42 [Abstract]

David W, Brown G. Foot and mouth disease in human beings. (Commentary) Lancet 2001 May 12;357(9267):1463

Davies G. The foot and mouth disease (FMD) epidemic in the United Kingdom 2001. Comp Immunol Microbiol Infect Dis 2002;25(5-6):331-43 [Abstract]

DEFRA (Department for the Environment Food and Rural Affairs, United Kingdom). Foot and mouth disease [Web page]

Domingo E, Baranowski E, Escarmis S, et al. Foot and mouth disease virus. Comp Immunol Microbiol Infect Dis 2002;25(5-6):297-308 [Abstract]

FAO (Food and Agricultural Organization of the United Nations). European Commission for the Control of Foot-and-Mouth Disease (EUFMD) map of recent outbreaks of FMD [Web page]

House J, Mebus CA. Foot-and-mouth disease. In: US Animal Health Association, Committee on Foreign Animal Disease. Foreign animal diseases: the gray book. Ed 6. Part IV. Richmond, VA: US Animal Health Assoc, 1998 [Full text]

Hughes GJ, Mioulet V, Kitching RP, et al. Foot-and-mouth disease virus infection of sheep: implications for diagnosis and control. Vet Rec 2002 Jun 8;150(23):724-7

Kitching RP. Foot-and-mouth disease. In: Aeillo S, ed. Merck veterinary manual. Ed 8. Whitehouse Station, NJ: Merck & Co, 1998 [Full text]

Lubroth J. Foot and mouth disease: a review for the practitioner. Vet Clin North Am Food Anim Pract 2002;18(3):475-99 [Abstract]

Murphy FA, Gibbs EP, Horzinek MC, et al. Picornaviridae. In: Veterinary virology. Ed 3. San Diego, CA: Academic Press, 1999:517-8

OIE (Office International des Epizooties/World Organization for Animal Health). Disease information in the last 18 months (recent outbreaks) [Web page—scroll to foot-and-mouth disease]

OIE (Office International des Epizooties/World Organization for Animal Health). Foot-and-mouth disease. In: Manual of standards for diagnostic tests and vaccines 2000. Chap 2.1.9 [Full text]

OIE (Office International des Epizooties/World Organization for Animal Health). List of foot and mouth disease free countries [Web page]

OIE (Office International des Epizooties/World Organization for Animal Health). OIE classification of diseases [Web page]

Paarlberg PL, Lee JG, Seitzinger AH. Potential revenue impact of an outbreak of foot-and-mouth disease in the United States, J Am Vet Med Assoc 2002 Apr 1;220(7):988-92 [Abstract]

Reid SM, Ferris NP, Hutchings GH, et al. Detection of all seven serotypes of foot-and-mouth disease virus by real-time, fluorgenic reverse transcription polymerase chain reaction assay. J Virol Meth 2002 Aug;105(1);67-80

Remond M, Kaiser C, Lebreton F. Diagnosis and screening of foot-and-mouth disease. Comp Immunol Microbiol Infect Dis 2002;25(5-6):309-20 [Abstract]

Tharratt RS, Case JT, Hird DW. Perceptions of state public health officers and state veterinarians regarding risks of bioterrorism in the United States. J Am Vet Med Assoc 2002 Jun 15;220(12):1782-7 [Abstract]

Toma B, Moutou F, Dufour B, et al. Ring vaccination against foot-and-mouth disease. Comp Immunol Microbiol Infect Dis 2002;25(5-6):365-72

Tomassen FH, de Koeijer A, Mourits MC, et al. A desicion-tree to optimize control measures during the early stage of foot-and-mouth disease epidemic. Prev Vet Med 2002 Aug 30;54(4):301-24 [Abstract]