Foot-and-Mouth Disease

Foot-and-mouth disease (FMD) is a highly contagious, acute, and often severe viral disease affecting all cloven-hoofed animals, including cattle, swine, sheep, goats, and wild ruminants. It is caused by a picornavirus of the genus Aphthovirus, and is characterized by the development of vesicles (blisters) in the oral cavity, on the muzzle, on the teats, and in the interdigital spaces of the feet. In dairy cattle, the disease leads to severe lameness, anorexia, fever, and a dramatic drop in milk production, often with a prolonged recovery period. The economic impact is enormous due to trade restrictions, culling of infected and contact animals, and loss of productivity. FMD is a notifiable disease in most countries, and its control is a priority for veterinary public health and international trade. The disease is endemic in many parts of the world, including Turkey, where it is known as 'Sap Hastaligi'. In cattle, the disease is particularly severe in high-producing dairy breeds, with morbidity rates approaching 100% in susceptible herds, although mortality is generally low (1-5%) except in young calves, where myocarditis can cause sudden death. The disease is a vesicular condition, and its clinical presentation must be differentiated from other vesicular diseases such as vesicular stomatitis, bovine viral diarrhea (BVD) with mucosal disease, and infectious bovine rhinotracheitis (IBR) with oral lesions. The pathogenesis involves viral replication in the pharyngeal epithelium and subsequent viremia, leading to vesicle formation in epithelial tissues. The incubation period is typically 2-14 days, and the virus is shed in large quantities in vesicular fluid, saliva, milk, and feces. The disease is transmitted by direct contact, aerosol, and fomites, and the virus can survive for long periods in the environment, especially in cool, moist conditions. Control measures include vaccination, movement restrictions, and stamping-out policies in FMD-free countries. In endemic areas, vaccination is the primary control strategy, and the use of inactivated vaccines is common. The disease is a major constraint to international trade in livestock and livestock products, and its presence can lead to severe economic losses for producers and national economies.

The causative agent of foot-and-mouth disease is Foot-and-mouth disease virus (FMDV), a non-enveloped, single-stranded positive-sense RNA virus belonging to the family Picornaviridae, genus Aphthovirus. There are seven immunologically distinct serotypes: A, O, C, SAT1, SAT2, SAT3, and Asia1. Within each serotype, there are numerous topotypes and strains, which vary in antigenicity and virulence. The virus is highly variable due to its RNA-dependent RNA polymerase lacking proofreading ability, leading to frequent mutations and antigenic drift. The virus is relatively labile in the environment, being inactivated by heat (above 50°C), ultraviolet light, and common disinfectants such as sodium hydroxide, sodium carbonate, and citric acid. However, it can survive for weeks in contaminated feed, bedding, and on fomites, especially in cool, humid conditions. The virus is present in high concentrations in vesicular fluid, saliva, milk, and feces of infected animals. The primary route of infection is respiratory, via inhalation of aerosolized virus, but ingestion and direct contact with contaminated materials are also important. The virus initially replicates in the pharyngeal and respiratory epithelium, then spreads to regional lymph nodes, and subsequently causes viremia, which disseminates the virus to epithelial tissues of the oral cavity, feet, and teats, where it causes vesicle formation. The virus has a high affinity for epithelial cells, and the cytopathic effect leads to the formation of vesicles. The virus is shed in milk for up to 4 days before clinical signs appear, and in semen, which is important for transmission via artificial insemination. The virus can also establish a persistent infection in the pharynx of ruminants, particularly in cattle, for up to 2 years, leading to the carrier state. The carrier state is a significant concern for disease control, as carriers can potentially transmit the virus to susceptible animals, although the risk is considered low. The virus is highly contagious, and the infectious dose is very low, with as little as 10-100 infectious particles being sufficient to cause infection in cattle.

Foot-and-mouth disease is endemic in many parts of the world, including Turkey, the Middle East, Africa, Asia, and parts of South America. The disease is highly contagious and can spread rapidly within and between herds. The morbidity rate in susceptible cattle herds is often 100%, but the mortality rate is generally low, typically less than 5%, except in young calves, where it can be higher due to myocarditis. The disease affects all breeds and ages of cattle, but the severity of clinical signs is often greater in high-producing dairy cattle, likely due to the stress of lactation and metabolic demands. The disease is more common in intensive production systems, such as dairy farms and feedlots, where animal density is high and movement of animals and personnel is frequent. The incubation period is 2-14 days, and the virus is shed in high quantities in vesicular fluid, saliva, milk, and feces. The virus can be transmitted by direct contact, aerosol, and fomites, including contaminated vehicles, equipment, and clothing. The virus can also be spread by wind over short distances, and by the movement of infected animals, which is the most common mode of spread. The disease is more prevalent in the cooler months, as the virus survives longer in the environment at lower temperatures. The economic impact of FMD is significant, with losses due to decreased milk production, weight loss, lameness, mastitis, and reproductive disorders. In addition, the disease leads to trade restrictions, which can have a devastating effect on the livestock industry. In endemic areas, vaccination is used to control the disease, but the effectiveness of vaccination is limited by the antigenic diversity of the virus and the need for regular booster vaccinations. The disease is a major concern for FMD-free countries, where an outbreak would lead to massive culling of animals and severe economic losses. The global distribution of FMD is influenced by the movement of animals and animal products, and the disease is considered a transboundary animal disease that requires international cooperation for control.

The pathophysiology of foot-and-mouth disease involves a complex interplay between viral replication, host immune response, and tissue damage. The virus enters the host through the respiratory tract, primarily via inhalation of aerosolized virus, or through ingestion or direct contact with contaminated material. The initial site of replication is the pharyngeal epithelium, particularly the tonsils and the dorsal surface of the soft palate. The virus then spreads to regional lymph nodes, where it replicates further, leading to a primary viremia. The viremia disseminates the virus to secondary sites of replication, which are primarily epithelial tissues of the oral cavity, feet, and teats. The virus has a high affinity for epithelial cells, and its replication leads to cell lysis and the formation of vesicles. The vesicles are characterized by the accumulation of fluid in the stratum spinosum of the epidermis, leading to the separation of the epidermal layers. The vesicles are fragile and rupture easily, leading to the formation of erosions and ulcers. The lesions are painful, leading to lameness, anorexia, and reluctance to move. The virus also causes damage to the myocardium, particularly in young animals, leading to myocarditis and sudden death. The host immune response involves the production of neutralizing antibodies, which are important for recovery and protection against reinfection. However, the virus can evade the immune response by antigenic variation and by establishing persistent infection in the pharynx. The persistent infection is characterized by the presence of the virus in the pharyngeal epithelium, particularly in the dorsal surface of the soft palate, for up to 2 years. The carrier state is associated with a low level of viral replication and the presence of viral RNA, but the exact mechanisms of persistence are not fully understood. The systemic effects of FMD include fever, which is due to the release of pyrogens, and a decrease in milk production, which is due to the combined effects of fever, anorexia, and the stress of the disease. The disease also leads to an increased susceptibility to secondary bacterial infections, such as mastitis and foot infections, which can complicate the clinical picture and prolong recovery.

Several factors predispose cattle to foot-and-mouth disease, including the immune status of the animal, the strain of the virus, and environmental and management factors. The most important predisposing factor is the lack of immunity, either due to no prior exposure or vaccination, or due to waning immunity from vaccination. The disease is more severe in young animals, particularly calves, due to their immature immune system and the higher susceptibility of the myocardium to viral damage. High-producing dairy cattle are also more susceptible to severe clinical signs, likely due to the stress of lactation and the metabolic demands of high milk production. The disease is more common in intensive production systems, where animal density is high and the risk of transmission is increased. Poor biosecurity practices, such as the movement of animals without quarantine, the sharing of equipment, and the lack of disinfection, increase the risk of introduction and spread of the virus. The disease is more prevalent in the cooler months, as the virus survives longer in the environment at lower temperatures. The presence of other diseases, such as parasitic infections or nutritional deficiencies, can also predispose cattle to more severe disease by compromising the immune system. The strain of the virus is also important, as some strains are more virulent than others, and the antigenic diversity of the virus can lead to vaccine failure. The use of vaccines that do not match the circulating strain can also predispose to disease, as the immunity provided by the vaccine may be incomplete. The movement of animals from endemic areas to FMD-free areas is a major risk factor for the introduction of the disease, and the lack of effective quarantine and testing can lead to outbreaks.

The clinical signs of foot-and-mouth disease in cattle typically appear 2-14 days after exposure to the virus. The first signs are often fever (up to 41°C), depression, and a decrease in milk production. Within 24-48 hours, vesicles develop in the oral cavity, particularly on the tongue, dental pad, and gums. The vesicles are small, fluid-filled blisters that are painful and rupture easily, leaving erosions and ulcers. The affected animals often drool saliva, have difficulty eating, and may refuse feed. Vesicles also develop on the feet, particularly in the interdigital space and on the coronary band. The affected animals are lame, reluctant to move, and may lie down for prolonged periods. The lameness is often severe, and the animals may have a characteristic 'paddling' gait. Vesicles may also develop on the teats, leading to mastitis and a further decrease in milk production. The lesions on the teats are painful and can lead to secondary bacterial infections. In severe cases, the animals may lose weight, and the disease can be fatal, particularly in young calves, where myocarditis can cause sudden death. The clinical signs are similar to those of other vesicular diseases, such as vesicular stomatitis, and a definitive diagnosis requires laboratory testing. The disease is highly contagious, and the presence of multiple animals with similar signs in a herd is a strong indication of FMD. The clinical signs can vary in severity depending on the strain of the virus and the immune status of the animal. In some cases, the disease may be subclinical, particularly in vaccinated animals, but these animals can still shed the virus and transmit the disease. The recovery period is typically 2-3 weeks, but the lesions can take longer to heal, and the animals may have a prolonged period of reduced productivity.

The differential diagnoses for foot-and-mouth disease in cattle include other vesicular diseases and conditions that cause oral lesions, lameness, and fever. The most important differential is vesicular stomatitis, which is caused by a rhabdovirus and is clinically indistinguishable from FMD. Vesicular stomatitis is endemic in the Americas and is transmitted by insects, and it causes similar vesicles in the oral cavity and on the feet. However, vesicular stomatitis is less contagious and has a lower morbidity rate. Another differential is bovine viral diarrhea (BVD) with mucosal disease, which can cause oral erosions and ulcers, but these are typically not vesicular and are accompanied by diarrhea and other systemic signs. Infectious bovine rhinotracheitis (IBR) can also cause oral lesions, but these are usually necrotic and not vesicular. Other conditions that can cause lameness and foot lesions include foot rot (interdigital necrobacillosis), which is a bacterial infection of the interdigital space, and laminitis, which is a metabolic condition. These conditions are not associated with vesicles and are usually less contagious. Bluetongue, a viral disease transmitted by midges, can cause oral lesions and lameness, but it is more common in sheep and is not typically vesicular. Malignant catarrhal fever can cause oral erosions and fever, but it is usually sporadic and not contagious. The diagnosis of FMD requires laboratory confirmation, as the clinical signs are not pathognomonic. The laboratory tests include virus isolation, antigen detection by ELISA, and molecular techniques such as RT-PCR. The samples for testing include vesicular fluid, epithelial tissue, and blood. The differential diagnosis is critical, as the presence of FMD has serious implications for trade and control measures.

The diagnostic algorithm for foot-and-mouth disease in cattle begins with a thorough herd history and clinical examination. The presence of vesicular lesions in the oral cavity, on the feet, and on the teats, along with fever, lameness, and a drop in milk production, is highly suggestive of FMD. The disease should be suspected in any animal with vesicular lesions, especially if multiple animals are affected and the herd is in an endemic area. The next step is to rule out other vesicular diseases, particularly vesicular stomatitis. The definitive diagnosis requires laboratory testing, and samples should be collected from affected animals. The samples include vesicular fluid, epithelial tissue from the lesions, and blood. The samples should be transported to a diagnostic laboratory under appropriate conditions, as the virus is labile. The laboratory tests include virus isolation, which is the gold standard, but it is time-consuming and requires specialized facilities. Antigen detection by ELISA is rapid and can be used for serotyping. Molecular techniques such as RT-PCR are highly sensitive and specific and can provide results within a few hours. The samples should be collected as early as possible in the course of the disease, as the virus is present in high concentrations in the vesicular fluid and epithelial tissue. The laboratory should be notified of the suspicion of FMD, as the disease is notifiable and requires immediate action. In addition to laboratory testing, the diagnostic algorithm includes the implementation of biosecurity measures to prevent the spread of the disease. The movement of animals and personnel should be restricted, and the premises should be quarantined. The diagnostic algorithm also includes the evaluation of the immune status of the herd, including vaccination history and the presence of antibodies. The results of the laboratory tests are used to confirm the diagnosis and to determine the serotype of the virus, which is important for the selection of the appropriate vaccine. The diagnostic algorithm is essential for the rapid and accurate diagnosis of FMD, which is critical for the control of the disease.

The laboratory findings in foot-and-mouth disease are primarily related to the detection of the virus or viral components, as well as the assessment of the host immune response. The most definitive laboratory finding is the isolation of the virus from vesicular fluid, epithelial tissue, or blood. The virus can be isolated in cell cultures, such as primary bovine thyroid cells or BHK-21 cells, and the cytopathic effect is typically observed within 24-48 hours. The virus can also be detected by antigen-capture ELISA, which is rapid and can be used to identify the serotype. Molecular techniques such as RT-PCR are highly sensitive and specific and can detect viral RNA in clinical samples. The samples for RT-PCR include vesicular fluid, epithelial tissue, and blood. The RT-PCR can also be used to determine the genetic characteristics of the virus, which is important for epidemiological investigations. Serological tests are used to detect antibodies against the virus, which can indicate previous exposure or vaccination. The tests include virus neutralization, ELISA, and complement fixation. The presence of antibodies in unvaccinated animals indicates infection, but in vaccinated animals, the interpretation is more complex. The laboratory findings also include the assessment of the host response, such as an increase in white blood cell count, but this is non-specific. In severe cases, there may be evidence of myocardial damage, such as elevated cardiac enzymes, but this is not commonly measured. The laboratory findings are essential for the confirmation of the diagnosis and for the implementation of control measures. The samples should be collected and transported according to the guidelines of the World Organisation for Animal Health (OIE), and the laboratory should be accredited for the diagnosis of FMD.

Imaging is not typically used in the diagnosis of foot-and-mouth disease, as the clinical signs and laboratory tests are sufficient for the diagnosis. However, imaging may be used to assess the extent of the lesions, particularly in the feet. Radiography can be used to evaluate the bones and joints of the feet, but it is not commonly performed. Ultrasonography can be used to assess the soft tissues of the feet, but it is not routinely used. In cases of myocarditis, echocardiography may be performed to assess cardiac function, but this is rare. The use of imaging is limited in the field, and the diagnosis is primarily based on clinical signs and laboratory tests. The imaging findings are not specific for FMD and are not used for the differential diagnosis. Therefore, imaging is not a standard part of the diagnostic workup for FMD.

Cytology and histopathology are not commonly used in the diagnosis of foot-and-mouth disease, as the diagnosis is based on clinical signs and laboratory tests. However, histopathology can be performed on tissue samples from the lesions, and it can provide supportive evidence of the disease. The histopathological findings include the presence of vesicles in the epidermis, with acantholysis and ballooning degeneration of epithelial cells. The vesicles are filled with fluid and contain inflammatory cells, including neutrophils and lymphocytes. The lesions are characterized by the separation of the epidermal layers, with the formation of clefts and bullae. The dermis may show edema and infiltration of inflammatory cells. In cases of myocarditis, histopathology of the heart muscle shows necrosis and inflammation. The histopathological findings are not pathognomonic for FMD, as similar lesions can be seen in other vesicular diseases. Therefore, histopathology is not used as a primary diagnostic tool, but it can be used to support the diagnosis. Cytology of vesicular fluid can be performed, and it typically shows the presence of epithelial cells and inflammatory cells, but it is not specific. The diagnosis of FMD is confirmed by laboratory tests, and histopathology is not routinely performed.

There is no specific antiviral treatment for foot-and-mouth disease, and the management of affected animals is primarily supportive. The treatment is aimed at alleviating the clinical signs, preventing secondary bacterial infections, and promoting recovery. The affected animals should be provided with soft, palatable feed and clean water, as the oral lesions can make eating difficult. The animals should be housed in a clean, dry environment to prevent secondary infections of the foot lesions. The foot lesions should be cleaned and treated with antiseptic solutions, and the animals should be provided with pain relief. Non-steroidal anti-inflammatory drugs (NSAIDs) such as flunixin meglumine or meloxicam can be used to reduce fever and pain. The dosage of flunixin meglumine is 1.1-2.2 mg/kg IV or IM, once daily, for up to 3 days. Meloxicam can be given at a dose of 0.5 mg/kg IV or SC, once. Antibiotics may be indicated to prevent or treat secondary bacterial infections, particularly in the feet and teats. The choice of antibiotic should be based on the suspected pathogens, and common choices include oxytetracycline, ceftiofur, and penicillin. The dosage of oxytetracycline is 10-20 mg/kg IM or SC, every 24-48 hours. Ceftiofur can be given at a dose of 2.2 mg/kg IM or SC, once daily. Penicillin G is given at a dose of 22,000 IU/kg IM, once daily. The use of antibiotics should be based on the clinical judgment and the presence of secondary infections. In severe cases, fluid therapy may be necessary to correct dehydration and electrolyte imbalances. The affected animals should be monitored closely, and the recovery period can take several weeks. The treatment is not a substitute for control measures, and the affected animals should be isolated to prevent the spread of the disease. In FMD-free countries, the treatment is not recommended, and the affected animals are culled as part of the stamping-out policy.

The prognosis for foot-and-mouth disease in cattle is generally good, with most animals recovering within 2-3 weeks. The mortality rate is low, typically less than 5%, but it can be higher in young calves, where myocarditis can cause sudden death. The prognosis is worse in animals with severe secondary bacterial infections, such as mastitis or foot infections, and in animals that are in poor body condition. The recovery period can be prolonged, and the animals may have a significant decrease in milk production, which may not return to pre-disease levels. The disease can also have long-term effects on reproductive performance, with an increased risk of abortion and reduced fertility. The prognosis is also influenced by the strain of the virus and the immune status of the animal. Vaccinated animals may have a milder form of the disease and a better prognosis. The economic impact of the disease is significant, and the prognosis for the herd is influenced by the control measures implemented. In FMD-free countries, the prognosis for the herd is poor, as the affected animals are culled. In endemic areas, the prognosis is better, as the animals can recover and develop immunity. The prognosis should be discussed with the owner, and the decision to treat or cull should be based on the individual animal's condition and the control policies in place.

The follow-up of animals affected by foot-and-mouth disease is important to monitor recovery and to prevent the spread of the disease. The affected animals should be monitored daily for the resolution of clinical signs, including the healing of lesions and the return of appetite and milk production. The animals should be isolated from the rest of the herd until they are fully recovered, which may take several weeks. The follow-up should include regular examination of the feet and teats for signs of secondary infections, and appropriate treatment should be provided if necessary. The milk production should be monitored, and the animals should be provided with a balanced diet to support recovery. The herd should be monitored for the presence of new cases, and the biosecurity measures should be maintained to prevent the introduction of the virus. The follow-up should also include the assessment of the immune status of the herd, and the vaccination program should be reviewed and updated if necessary. The follow-up is also important for the surveillance of the disease, and the presence of any new cases should be reported to the veterinary authorities. The follow-up should be continued for at least 2-3 weeks after the last case, and the herd should be considered free of the disease only after a thorough examination and laboratory testing. The follow-up is essential for the control of the disease and for the prevention of future outbreaks.

Clinical pearls: 1. Foot-and-mouth disease should be suspected in any cattle with vesicular lesions in the oral cavity, on the feet, or on the teats, especially if multiple animals are affected and the herd is in an endemic area. 2. The disease is highly contagious, and immediate biosecurity measures should be implemented to prevent the spread. 3. The diagnosis should be confirmed by laboratory testing, as the clinical signs are similar to other vesicular diseases. 4. The treatment is supportive, and the use of NSAIDs can help reduce fever and pain. 5. The prognosis is generally good, but the disease can have a significant economic impact. Pitfalls: 1. Failure to suspect FMD can lead to rapid spread of the disease and severe economic losses. 2. The use of antibiotics without a clear indication can lead to antimicrobial resistance. 3. The movement of animals and personnel without proper biosecurity can spread the disease. 4. The failure to report the disease to the veterinary authorities can have legal consequences. 5. The use of vaccines that do not match the circulating strain can lead to vaccine failure and the continued spread of the disease.

There is no specific antiviral treatment for foot-and-mouth disease, and the use of drugs is primarily supportive. The following are the current drug protocols based on Plumb's Veterinary Drug Handbook and AABP guidelines: 1. Flunixin meglumine: 1.1-2.2 mg/kg IV or IM, once daily, for up to 3 days. Withdrawal time: milk 36 hours, meat 4 days. 2. Meloxicam: 0.5 mg/kg IV or SC, once. Withdrawal time: milk 5 days, meat 15 days. 3. Oxytetracycline: 10-20 mg/kg IM or SC, every 24-48 hours. Withdrawal time: milk 72 hours, meat 28 days. 4. Ceftiofur: 2.2 mg/kg IM or SC, once daily. Withdrawal time: milk 0 hours, meat 3 days. 5. Penicillin G: 22,000 IU/kg IM, once daily. Withdrawal time: milk 72 hours, meat 10 days. 6. Fluid therapy: Isotonic fluids such as lactated Ringer's solution or normal saline, IV, at a rate of 20-40 mL/kg over 1-2 hours, as needed. 7. Topical antiseptics for foot lesions: Povidone-iodine solution or chlorhexidine solution, applied to the affected areas. The use of these drugs should be based on the clinical judgment and the presence of secondary infections. The withdrawal times should be followed to ensure the safety of milk and meat for human consumption.

The literature on foot-and-mouth disease is extensive, and the disease is one of the most studied animal diseases due to its economic importance. Key landmark studies include the characterization of the virus and its serotypes, the development of vaccines, and the evaluation of control strategies. The World Organisation for Animal Health (OIE) provides guidelines for the diagnosis and control of FMD, and the disease is a notifiable disease in most countries. The use of vaccination is a key control strategy in endemic areas, and the effectiveness of vaccination has been demonstrated in several studies. However, the antigenic diversity of the virus and the need for regular booster vaccinations are challenges. The use of stamping-out policies in FMD-free countries has been effective in eradicating the disease, but it is costly and controversial. The development of new vaccines, such as recombinant vaccines, is an area of active research. The use of antiviral drugs is not recommended, and the treatment is primarily supportive. The economic impact of FMD has been quantified in several studies, and the disease can cause significant losses to the livestock industry. The literature emphasizes the importance of early detection and rapid response to prevent the spread of the disease. The use of molecular techniques, such as RT-PCR, has improved the diagnosis and surveillance of FMD. The carrier state is a concern, and the risk of transmission from carriers is low but not negligible. The literature also highlights the importance of biosecurity measures in preventing the introduction and spread of the disease. Overall, the evidence-based literature supports the use of vaccination and biosecurity as the main control measures, and the importance of international cooperation in the control of FMD.