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Chapter 7 Viral zoonoses.

PICORNAVIRUSES

Overview

Picornaviruses are among the smallest (pico is Greek for small and rna for its RNA core), most diverse (more than 200 serotypes), and oldest known viruses. Poliomyelitis virus, a member of the Picornaviridae family, was one of the first recorded infections with evidence found in an Egyptian tomb on a stone tablet of a drawing depicting a man with deformities typical of paralytic poliomyelitis. No civilization or culture has escaped polio infection with people such as Sir Walter Scott, Franklin Delano Roosevelt, and Itzhak Perlman afflicted with this disease. Poliomyelitis was first recognized to be caused by a virus by Landsteiner and Popper in 1909, but the virus was not isolated until the 1930s. The polio epidemics of the 1930s and 1940s aided in the understanding of picornaviruses in general.

Viruses in the Picornaviridae family cause an extraordinarily wide range of diseases, have narrow host ranges and are typically transmitted horizontally (are not passed on from parent to offspring). Syndromes associated with these agents include asymptomatic infection, aseptic meningitis syndrome, colds, febrile illnesses with rashes, conjunctivitis, and hepatitis. There are nine genera of picornaviruses: Enterovirus (poliovirus, swine vesicular disease, coxsackievirus (which causes hand-foot-and-mouth disease in humans), and enterovirus A), Rhinovirus (human and bovine rhinoviruses), Hepatovirus (hepatitis A virus), Aphthovirus (foot-and-mouth disease virus in cattle), Cardiovirus (encephalomyocarditis virus in mice), Erbovirus (equine rhinitis B virus), Kobuvirus (Aichi kobuvirus), Teschovirus (porcine teschovirus), and Parechovirus (human parechovirus, which was formerly known as Echovirus 22 and 23). Of these viruses, only swine vesicular disease virus, foot-and-mouth disease virus, and encephalomyocarditis virus are zoonotic. In 1898, Friedrick Loeffler and Paul Frosch isolated foot-and-mouth disease virus in cattle, one of the first viruses isolated. Foot-and-mouth disease is a highly contagious, acute infection of cloven-hooved animals producing vesicular lesions and erosions in the mouth, nares, muzzle, feet, teats, udder, and rumen. Swine vesicular disease is a transient disease mainly found in cattle, pigs, and horses that produces vesicular lesions in the mouth and on the feet. Encephalomyocarditis virus causes neurologic and cardiac disease in mice and rats and can be transmitted to swine. Although there have been outbreaks of poliomyelitis virus in wild monkeys, monkeys are not a source of human poliomyelitis and is not considered zoonotic.

Causative Agent

All viruses of the Picornaviridae family are small (22 to 30 nm), single-stranded, positive sense RNA viruses that lack a lipid envelope (nonenveloped) and are icosahedral in shape. Areas of viral replication vary with the genus and include the epithelium of the nasopharynx and regional lymphoid tissue, conjunctiva, and intestines (Enterovirus), the nasopharyngeal epithelium and regional lymph nodes (Rhinovirus), and the intestinal epithelium progressing to viremia with blood transport of the virus to the liver (Hepatovirus). The areas of viral replication affect the route of transmission of picornaviruses and include fecal-oral (Enterovirus) and respiratory droplets (Rhinovirus).

Foot-and-Mouth Disease

Overview

Foot-and-mouth disease (FMD, Aphtae epizooticae in Latin, Fiebre Aftosa in Spanish, hoof-and-mouth disease) is a highly contagious and sometimes fatal viral disease mainly of cattle and pigs but can affect other cloven-hooved animals such as deer, goats, and sheep, as well as elephants, rats, and hedgehogs. There has been a high incidence of FMD in animals; however, human disease is rare. When FMD was endemic in Central Europe many vesicular diseases in humans with mouth and hand lesions were called FMD that may or may not have been FMD. The first human infection with FMD was reported in 1695 by Valentini in Germany. In 1897 Friedrich Loeffler determined that the cause of FMD was viral by passing the blood of an infected animal through a fine porcelain-glass filter and found that the filtered fluid could still cause the disease in healthy animals. In 1834, Hertwig infected three veterinarians with FMD. These veterinarians drank 250 milliliters of milk from infected cows on four consecutive days and then developed clinical disease. The first U.S. outbreak of FMD occurred in 1870 in New England and originated from imported livestock, as did outbreaks in 1880 and 1884 (all of these outbreaks were mild and contained). In October 1914 the largest U.S. outbreak of FMD spread rapidly throughout the Chicago stockyards and other markets affecting more than 3,500 livestock herds in 22 States and the District of Columbia before the outbreak was contained in September 1915. There have been nine U.S. outbreaks of FMD in 1870, 1880, 1884, 1902, 1905, 1908, 1914, 1924, and 1929 before being eradicated from the United States. The last United States outbreak of FMD occurred in California in 1929. FMD first appeared in the United Kingdom in 1839. After World War II, FMD was widely distributed throughout the world. In 1967 and 1968 FMD outbreaks in the U.K. led to the slaughter of more than 430,000 animals and by 1989 following a successful vaccination program Europe was deemed FMD-free. Once Europe was declared FMD-free vaccination of animals ceased. In February 2001 an epizootic in the United Kingdom that originated in Little Warley in Essex spread across Britain in 2 weeks and resulted in the destruction of more than 1 million animals. This epizootic began on a farm where restaurant scraps from a Chinese restaurant were fed to pigs (which was illegal).
As a result of their extremely small
size, approximately 500,000,000
picornaviruses could fit side by side on
the head of a pin.


Causative Agent

FMD is caused by a virus in the Aphthovirus genus of the viral family Picornaviridae. The members of the Picornaviridae family are small, nonenveloped, icosahedral, positive sense viruses that contain single-stranded RNA (Figure 7-29). There are seven different FMD serotypes, O, A, C, SAT-1 (SAT stands for South African Territories), SAT-2, SAT-3 and Asia-1, that show some regionality. Serotypes A, O, and C are referred to as European types because they were first isolated in France and Germany; however, they occur in other regions such as South America. Type O is the most common serotype. There is no serologic cross-reaction between these serotypes. There are numerous variants and subtypes within each serotype.
Horses are not susceptible to
FMD.


[FIGURE 7-29 OMITTED]

Epizootiology and Public Health Significance

FMD occurs worldwide with the exception of Australia, New Zealand, and North America. FMD occurs most commonly in Asia, Africa, the Middle East, and South America. SAT-1 to SAT-3 are predominantly found in Africa; Asia-1 is only found in Asia, and types A, O, and C are found in Europe and South America. Many countries in Europe have been FMD-free for almost 30 years; the last major outbreaks in Europe occurred in Denmark in 1988 and in England and France in 2001.
Foot-and-mouth disease is not to be
confused with hand, foot, and mouth
disease, which affects people producing
a rash on the hands and feet and in
the mouth. FMD is often confused
with Coxsackie A virus (hand, foot, and
mouth disease), herpes simplex, and
vesicular stomatitis.


FMD is endemic in animals in parts of Asia, Africa, the Middle East and South America. In 2001 FMD spread through farms in the United Kingdom leading to quarantines, the mass slaughter of animals, and the accumulation of agricultural damages amounting to an estimated $4.4 billion. The last large-scale outbreak of FMD in the United States occurred in 1929 and neither Canada nor Mexico has had an outbreak since the 1950s. However, a single FMD case would instantly shut down the export of all animal products. Morbidity can be 100% in a susceptible population. The mortality rate in adult cattle is 2% to 3%; in calves the mortality rate can be up to 40%. FMD is rare in humans and its economic impact is seen with trade embargoes rather than human disease.

Transmission

FMD is acquired by inhalation and ingestion. It is spread by contact (directly by animals or indirectly by fomites) or passively by vectors, aerosol, and contaminated water. Rodents, birds, animals, and humans can spread the virus as a result of the persistence of the virus in animals (6 months or more) and the high stability of the virus. Humans are typically infected by direct handling of infected animals or animal contact during slaughter. FMD virus can survive up to 24 hours in the human respiratory tract and is the reason people are kept away from infectious farms and their animals. Laboratory infections are possible and human-to-human transmission is rare.

Sheep and goats are maintenance hosts showing very mild signs. Pigs exhale FMD virus in higher concentrations than other species (thousands of times more concentrated) and are considered amplifying hosts. Cattle can be indicators of disease because they are typically the first species to show clinical signs of FMD.

Pathogenesis

When a picornavirus, like all RNA viruses, come in contact with a host cell, it binds to a receptor site and enters the host cell through invagination of the cell membrane. Once the virus is inside the host cell, its protein coat dissolves and new viral RNA is synthesized in large quantities and assembled to form new viruses. After assembly, the host cell lyses and releases the new viruses. The specific lesions of FMD are microscopic in the early stages and are found in the epithelium. Lesions start with degeneration of cells in the middle of the epithelial layers with epithelial cells becoming round and detached from one another. Edema forms between the cells and separates them. Neutrophils infiltrate the epithelium, serum accumulates in the area, and leukocytes (WBCs) produce fluid filled vesicles. The small vesicles coalesce to form bullae causing large areas of epithelium to detach and to be shed (or rubbed off). Epithelial loss is most common on the dorsal surface of the rostral two-thirds of the tongue in cattle. Epithelial loss results in a raw, red, painful area that causes anorexia in affected animals. Later in the disease the vesicles can contain necrotic epithelial cells, leukocytes, erythrocytes, and sometimes bacteria. Lesions can also be seen in the myocardium (young calves and lambs) and skeletal muscle.

Clinical Signs in Animals

After contact with infected animals, clinical signs will appear in newly infected animals in 3 to 5 days. FMD is characterized by high fever and blisters inside the mouth that can lead to excessive secretion of stringy or foamy saliva. Blisters are typically 2 mm to 10 cm in diameter and can also appear on the nares, muzzle, feet, or teats. Blisters on the feet may rupture and cause lameness. Adult animals may suffer weight loss that can last for several months, pregnant animals may abort as a result of the high fever, and testicles of mature males can swell. Most animals eventually recover from FMD in approximately 2 weeks with mortality rates being low. Complications can occur and include myocarditis and death, especially in newborn animals. Some infected animals become carriers of FMD and can transmit it to other animals. Clinical signs in specific species include:

* Cattle. A significant drop in milk production can occur in cows. In cattle, oral vesicular lesions are common on the tongue, dental pad, gums, soft palate, nares, and muzzle (Figure 7-30). Oral lesions result in excessive drooling and serous nasal discharge. Hoof lesions are seen in the coronary band and inter-digital space and may make the animal reluctant to move.

* Pigs. Hoof lesions are severe with vesicles on the coronary band, heel, and interdigital space. Vesicles may also appear on the snout. Oral lesions and drooling are not as common in pigs as they are in cattle.

* Sheep and goats. FMD is mild in sheep and goats producing low grade fever, oral lesions, and lameness.

[FIGURE 7-30 OMITTED]

Clinical Signs in Humans

FMD in humans is biphasic. After an incubation period of 2 to 8 days, symptoms including malaise, fever, nausea, vomiting, red painful ulcerative lesions of the oral mucous membranes, and sometimes vesicular lesions of the skin are seen. Erosions remain after the vesicles dry up. Most skin lesions heal in 5 to 10 days. The virus always enters through defects in the skin or oral mucous membranes producing a primary vesicle at the infection site. Viral dissemination occurs after the initial infection.
FMD virus does not cross the
placenta.


Diagnosis in Animals

FMD is suspected based on clinical signs of salivation and lameness associated with vesicles. Before collecting or sending samples from animals with vesicular disease, the proper authorities should be contacted. All samples should be collected and handled with appropriate precautions. Acceptable clinical specimens include vesicular fluid, affected mucous membranes, pharyngeal and esophageal fluid, blood, and serum. FMD is confirmed clinically by detecting antibodies in serum using ELISA and complement fixation serologic testing. Virus isolation to detect antigen or RT-PCR tests need to be done to confirm the first case of FMD within a facility. Virus isolation is done by inoculation of bovine thyroid cells, inoculation of pig, calf, and lamb kidney cells, or inoculation of mice. Mouse inoculation is done on suckling mice inoculated intraperitoneally with liquid from vesicles and if the material is positive the mice die in a few days. There is not an acceptable method for distinguishing between vaccinated and naturally-infected animals.
Since 1921, approximately
40 human cases of FMD have
been diagnosed.


Diagnosis in Humans

FMD is diagnosed in people using virus-neutralizing antibodies or ELISA tests.

Treatment in Animals

There is no treatment for FMD in animals. State and federal veterinarians need to be contacted immediately if any vesicular disease is observed in animals. Adult animals may need to be culled if the hoof wall becomes separated. Recommendations for control and eradication of the disease include strict quarantine and disinfection of the property.

Treatment in Humans

There is no treatment for FMD in people and therapy is symptomatic. Antibiotics may be needed for secondary infections.

Management and Control in Animals

One way to control FMD in animals is by vaccination. FMD vaccines given either prophylactically or to control an outbreak must closely match the serotype and subtype the animal will be exposed to. With 7 serotypes and more than 60 subtypes there is no universal FMD vaccine. The United States, Canada, and Mexico maintain the North American FMD Vaccine Bank, which contains vaccine strains for the most prevalent serotypes worldwide. The North American FMD Vaccine Bank is located at the USDA Foreign Animal Disease Diagnostic Laboratory (FADDL) at Plum Island Animal Disease Center. The Chief Veterinary Officer of each country would make the decision as to the use of vaccination to control an outbreak. A formalin-inactivated vaccine against serotypes A, C, and O was used in Europe prior to 1990; however, it was discontinued because the seroconversion was not sufficient to provide protection against contracting FMD. Ethylenimine-inactivated virus vaccines grown in BHK (baby hamster kidney) cells are currently used in at-risk countries. There are currently three disease states regarding FMD: FMD present with or without vaccination, FMD free with vaccination, and FMD free without vaccination. Countries designated as FMD free without vaccination have the greatest access to export markets, making this status the most desirable.

The USDA bans the import of animals and animal products from known FMD-infected areas. The USDA also monitors all ports of entry to the United States, requiring passengers who have traveled in affected areas to disinfect their shoes. They also search luggage and cargo for the presence of products that could spread FMD.

When FMD outbreaks occur, the movement of animals and animal products is halted, infected animals and contact animals are slaughtered and their carcasses disposed of, vehicles and personnel leaving the infected area are disinfected, and ring vaccination of nearby animals may be done to create a buffer zone. Vaccination is only allowed in some countries during outbreaks and only with a special permit.

Management and Control in Humans

People can avoid FMD virus infection by proper individual hygiene (wearing gloves and protective clothing). FMD is not a serious public health concern as a result of the low number of cases seen to date.
On June 18, 1981, the U.S. government
announced the creation of vaccine
targeted against FMD, which was the
world's first genetically engineered
vaccine.


Summary

Foot-and-mouth disease (FMD) is a highly contagious and sometimes fatal viral disease mainly of cattle and pigs but can affect other cloven-hooved animals such as deer, goats, and sheep. There has been a high incidence of FMD in animals; however, human disease is rare. FMD is caused by a virus in the Aphthovirus genus of the viral family Picornaviridae. There are seven different FMD serotypes, O, A, C, SAT-1, SAT-2, SAT-3 and Asia-1. There is no serologic cross-reaction between these serotypes and there are numerous variants and subtypes within each serotype. FMD occurs worldwide with the exception of Australia, New Zealand, and North America. FMD is acquired by inhalation and ingestion. It is spread by contact or passively by vectors, aerosol, and contaminated water. Humans are typically infected by direct handling of infected animals or animal contact during slaughter. After contact with infected animals, clinical signs will appear in newly infected animals in 3 to 5 days. FMD is characterized by high fever and blisters inside the mouth that can lead to excessive secretion of stringy or foamy saliva. Blisters are typically 2 mm to 10 cm in diameter and can also appear on the nares, muzzle, feet, or teats. Most animals eventually recover from FMD in approximately 2 weeks with mortality rates being low. Complications can occur and include myocarditis and death, especially in newborn animals. Clinical signs in specific species include a significant drop in milk production in cows, oral lesions resulting in excessive drooling and serous nasal discharge in cattle, vesicles on the snout in pigs, oral lesions and drooling in pigs (less than in cattle), and mild signs such as low grade fever, oral lesions, and lameness in sheep and goats. FMD in humans is biphasic producing symptoms such as malaise, fever, nausea, vomiting, red painful ulcerative lesions of the oral mucous membranes, and sometimes vesicular lesions of the skin. Before collecting or sending samples from animals with vesicular disease, the proper authorities should be contacted. FMD in animals is confirmed using ELISA and complement fixation serologic testing (antibody detection), virus isolation to detect antigen, or RT-PCR tests to detect nucleic acids. FMD is diagnosed in people using virus-neutralizing antibodies or ELISA tests. There is no treatment for FMD in animals. State and federal veterinarians need to be contacted immediately if any vesicular disease is observed in animals. Recommendations for control and eradication of the disease include strict quarantine and disinfection of the property. There is no treatment for FMD in people and therapy is symptomatic. One way to control FMD in animals is by vaccination. The USDA bans the import of animals and animal products from known FMD infected areas. People can avoid FMD virus infection by proper individual hygiene.

Swine Vesicular Disease

Overview

Swine vesicular disease (SVD), also known as porcine enterovirus infection, is a contagious viral disease of pigs that produces clinical signs similar to foot-and-mouth disease. SVD produces vesicles on the coronary band, heels of the feet and occasionally on the lips, tongue, snout, and teats. SVD was first reported in feeder pigs in Lombardy, Italy, in 1966. The origin of this viral disease is unknown, but it has been suggested that it is derived from a human enterovirus. Since 1966 SVD has been seen in Hong Kong, Japan, and Western European countries. The first outbreak of SVD in Great Britain was in 1972 resulting in 532 cases involving a total of 322,081 pigs over a 10-year period. SVD was eradicated from Great Britain in 1982. SVD has persisted in Italy especially in an enzootic form in the southern part of the country, where there were 171 outbreaks in 2002. The rest of Europe is currently free of SVD except for Portugal who had 2 cases early in 2004. Since 2000 SVD has only been seen in Portugal and Italy. In the United States there was an outbreak of SVD in 1982 to 1983 in which 600 premises in 14 states were affected. In 1995 another SVD outbreak occurred involving 365 premises in 5 states.

Causative Agent

Swine vesicular disease is caused by a virus in the Enterovirus genus of the viral family Picornaviridae. The members of the Picornaviridae family are small, non-enveloped, positive sense, icosahedral viruses that contain single-stranded RNA. SVD virus is antigenically similar to the human enterovirus Coxsackie B-5 (which is classified as the human enterovirus B). Despite consisting of a single serotype, swine vesicular disease virus (SVDV) shows a high genetic and antigenic variability. The virion capsid consists of a nonenveloped protein shell, which is made up of one copy of each of the four structural proteins VP1, VP2, VP3 and VP4. SVDV isolates are classified in four groups based on nucleotide sequencing with groups 1 and 2 being more closely related to each other than groups 3 and 4. Some SVDV isolates are nonpathogenic, whereas virulent isolates produce typical lesions in infected pigs.
SVD presents clinically identical to
foot-and-mouth disease; however, SVD
only occurs in pigs.


Epizootiology and Public Health Significance

SVD was seen in Italy, England, Scotland, Wales, Malta, Austria, Belgium, France, the Netherlands, Germany, Poland, Switzerland, Greece, and Spain, but has been eradication from all European countries. SVD is still seen in countries in the Far East.
SVDV is unrelated to other known
porcine enteroviruses.


The monetary losses from weight loss in pigs and piglet mortality from SVD do not produce a significant economic impact. The cost of SVD surveillance and control is greater than loss to farmers; however, surveillance and control is needed to avoid any confusion between SVD and foot-and-mouth disease. SVD rarely causes human disease and does not pose a significant threat on human health. Vesicular diseases in animals are summarized in Table 7-13.

Transmission

SVD virus is spread via ingestion of contaminated meat scraps and contact with infected animals or their infected feces. Virus is spread from the pig's nose, mouth, and feces for up to 48 hours before clinical signs are seen. Viral shedding from the feces can occur for up to 3 months following infection. The virus can survive for long periods in the environment and for up to 2 years in lymphoid tissue contained in dried, salted, or smoked meat.

Pathogenesis

Once SVDV gets into the body it has a predilection for epithelial tissue producing changes in the stratified epithelium of the skin of the coronary band, the metatarsals and metacarpals, snout, tongue, and tonsil. Coagulation necrosis results in vesicle formation and sloughing followed by hyperplasia of epithelial tissue. Necrosis of intradermal sweat glands may result in leukocyte accumulation.

Clinical Signs in Animals

The incubation period for SVD is 2 to 7 days following exposure to infected pigs and 2 to 3 days after ingestion of contaminated feed. Pigs with SVD have clinical signs similar to foot-and-mouth disease including fever, salivation, and lameness. Vesicles and erosions may be seen on the snout, mammary glands, coronary band, and interdigital areas of the feet (Figure 7-31). Vesicles are rarely found in the oral cavity. The infection in pigs may be subclinical, mild, or severe. Severe signs may be seen in pigs housed on damp concrete and in young pigs. Neurologic signs may be seen with the severe form of SVD producing clinical signs such as shivering, ataxia, and chorea (rhythmic jerking) of the limbs. Abortion in pregnant animals is rare. Recovery typically occurs in 2-3 weeks.

[FIGURE 7-31 OMITTED]

Clinical Signs in Humans

Human infections of SVD rarely produce clinical signs. Clinically inapparent infection can be seen in people who handle pigs. Seroconversion and mild clinical disease has been seen in laboratory workers. One human case of meningitis has been seen in a laboratory worker.

Diagnosis in Animals

SVD is suspected based on clinical signs of salivation and lameness associated with vesicles. Before collecting or sending samples from animals with vesicular disease, the proper authorities should be contacted. All samples should be collected and handled with appropriate precautions. SVD is confirmed using ELISA, direct complement fixation, virus neutralization, and virus isolation in pig-derived cell culture. RT-PCR is also available.

Diagnosis in Humans

SVD is suspected in people with close contact with pigs and is confirmed by virus isolation or antibody detection. Serologic testing for SVD in people is complicated by its close relationship to coxsackievirus B-5.

Treatment in Animals

There is no treatment for SVD in animals.

Treatment in Humans

There is no treatment for SVD in people and therapy is symptomatic.

Management and Control in Animals

When SVD outbreaks occur, infected farms or areas are quarantined. State and federal veterinarians need to be contacted immediately if any vesicular disease is observed in animals. Animals in contact with infected animals should be culled and properly disposed of. Recommendations for control and eradication of the disease include strict quarantine and disinfection of the property. Sodium hydroxide (1% with detergent), oxidizing agents, and iodophors work well against SVD virus.

Management and Control in Humans

People can avoid contracting SVD virus by using proper individual hygiene (wearing gloves and protective clothing) when handling infected pigs. SVD is not a serious public health concern because of the low number of cases seen to date.

Summary

Swine vesicular disease (SVD) is a contagious viral disease of pigs that produces clinical signs similar to foot-and-mouth disease. SVD produces vesicles on the coronary band, heels of the feet and occasionally on the lips, tongue, snout and teats. SVD is caused by a virus in the Enterovirus genus of the viral family Picornaviridae. SVD virus is antigenically similar to the human enterovirus Coxsackie B-5 (which is classified as the human enterovirus B). SVD was seen in many European countries, but has only been seen in Italy and Portugal since 2000. SVD is still seen in countries in the Far East. SVD virus is spread via ingestion of contaminated meat scraps and contact with infected animals or their infected feces. Pigs with SVD have clinical signs similar to foot-and-mouth disease including fever, salivation, and lameness. Vesicles and erosions may be seen on the snout, mammary glands, coronary band, and interdigital areas of the feet. The infection in pigs may be subclinical, mild, or severe. Human infections of SVD rarely produce clinical signs. Clinically inapparent infection can be seen in people who handle pigs. Seroconversion and mild clinical disease has been seen in laboratory workers. SVD is suspected in animals based on clinical signs of salivation and lameness associated with vesicles. SVD is confirmed using ELISA, direct complement fixation, virus neutralization, and virus isolation in pig-derived cell culture. RT-PCR is also available. SVD is suspected in people with close contact with pigs and is confirmed by virus isolation or antibody detection. There is no treatment for SVD in animals. State and federal veterinarians need to be contacted immediately if any vesicular disease is observed in animals. There is no treatment for SVD in people and therapy is symptomatic. When SVD outbreaks occur, infected farms or areas are quarantined. Infected pigs and pigs in contact with infected pigs should be slaughtered and properly disposed of. The premises should be disinfected. People can avoid contracting SVD virus by using proper individual hygiene when handling infected pigs. For information on less common zoonotic Picornaviruses, see Table 7-14.

POXVIRUSES

Overview

Viruses in the family Poxviridae produce disease associated with the production of pox on the skin. Pox are small eruptive skin pustules that may scar upon healing. Poxvirus infections have been present since antiquity with the first evidence of smallpox (the best known poxvirus) found in Egyptian mummies of the 18th Dynasty (1580-1350 B.C.). Smallpox endemics occurred in India in the first millennium B.C. and spread to Asia and, ultimately, to Europe in the 8th century. The introduction of smallpox to the New World in the 15th and 16th centuries decimated the Native American populations and had been used by the British as a biological weapon in the French-Indian wars. Smallpox was a worldwide problem into the 20th century (causing up to a half million deaths in Europe annually). In the 20th century an intense vaccination program eradicated smallpox. The last outbreak of smallpox occurred in 1977 in Somalia, and the WHO certified eradication in 1980. Two known stocks of variola virus exist: one at the CDC in Atlanta, Georgia, and the other in the former USSR.

Smallpox virus was used in vaccines when it was discovered that cutaneous exposure to dried smallpox lesions caused a milder smallpox infection in these people (this process was called variolization and unfortunately led to disease and death in addition to immunologic protection). In the 19th century, Jenner discovered that inoculation of people with cowpox virus led to smallpox immunity. This observation about immunity established the practice of vaccination. There are many other types of poxviruses that infect animals and humans. These other poxvirus infections are important to understand because their lesions must be differentiated from those of smallpox.

Causative Agent

Poxviruses are enveloped, linear, double-stranded DNA viruses in the order Caudovirales and family Poxviridae. Poxviruses are the largest and most complex of all viruses and are divided into two subfamilies: the Chordopoxvirinae (with eight genera) and the Entomopoxvirinae (with three genera). The Chordopoxvirinae are poxviruses of the vertebrates and the Entomopoxvirinae are the poxviruses of insects. The eight Chordopoxvirinae genera include Orthopoxvirus, Parapoxvirus, Yatapoxvirus, Molluscipoxvirus, Avipoxvirus, Capripoxvirus, Leporipoxvirus, and Suipoxvirus.

Poxviruses are the largest animal viruses and can be visualized via light microscopy. Poxvirus is oval or brick-shaped, between 200 to 400 nm in length, and composed of an external coat containing lipid and tubular or globular protein structures enclosing one or two lateral bodies and a core, which contains the genome (Figure 7-32). Poxviruses contain more than 30 structural proteins and several viral enzymes. Hemagglutinin is produced only by orthopoxviruses. Instead of a capsid, poxviruses have a nucleosome, which contains DNA and is surrounded by its own membrane. Poxviruses have a large number of NS (nonstructural) proteins, which are important for replication and pathogenesis. These viruses multiply in specialized parts of the host cell cytoplasm called the viroplasm, where they can cause skin lesions.

[FIGURE 7-32 OMITTED]

Contagious Ecthyma

Overview

Contagious ecthyma (CE) is a highly contagious, acute viral disease of sheep, goats, and wild ungulates that is known by a variety of other names such as orf, soremouth, scabby mouth, contagious pustular dermatitis, infectious labial dermatitis, and contagious pustular stomatitis. The term ecthyma comes from the Greek word ekthyma meaning pustule, which describes the deeper lesions associated with this disease. Orf is the name given to the human form of the disease, but will occasionally be used to describe the disease in animals. Infection by the contagious ecthyma virus was first described in sheep by Steeb in 1787 and in goats in 1879. The first case in humans was reported by Newson and Cross in 1934. CE is seen in countries that raise sheep and may be seen in any age sheep, but lambs are more susceptible. There is an antigenically distinct virus that causes CE in goats with more severe clinical signs than those found in sheep. CE can also be found in other ungulates such as camels, reindeer, and oxen.
Contagious ecthyma should not be
confused with ecthyma, an ulcerative
pyoderma usually caused by a
Streptococcus bacterial infection at the
site of minor trauma.


Causative Agent

CE is caused by the contagious ecthyma virus (also known as orf virus and Parapoxvirus ovis) in the Poxviridae family and Parapoxvirus genus (which also includes the milker's nodule virus (pseudocowpox) and bovine papular stomatitis virus). Parapoxviruses are large, enveloped, double-stranded DNA viruses with a regular surface structure that has spiral criss-crossing tubules (often described as a ball of wool structure), which differs from the other poxviruses. Parapoxviruses cause skin diseases and consists of five species and three tentative species including bovine papular stomatitis virus (BPSV), contagious ecthyma virus or Parapoxvirus ovis (PPVO), parapoxvirus of red deer in New Zealand (PVNZ), pseudocowpox virus (PCPV), and squirrel parapoxvirus (SPPV), as well as the tentative species auzdyk disease virus, chamois contagious ecthyma virus, and sealpox virus. PPVO is ovoid in shape and is one of the smallest viruses in the Poxviridae family.

Epizootiology and Public Health Significance

CE is found worldwide in countries that raise sheep. In the United States CE occurs most often in the Western states. A higher frequency of CE is found in Europe and New Zealand compared with North America. CE is an extremely infectious disease in animals with up to 90% of a flock showing clinical signs. Most infected animals will have mild loss of condition caused by anorexia from the painful condition of their mouths. Young lambs and kids may not eat and may die from malnutrition as a result of painful oral lesions or to abandonment by their mothers who have painful teat and udder lesions. Morbidity rates in unvaccinated flocks may be approximately 80%. CE is more severe in goats than sheep.

CE is more commonly seen in people who have close contact with sheep and goats (herd workers, shearers, veterinarians, butchers, and slaughter house workers). Most infected people develop a single lesion that will resolve in 3 to 6 weeks. No human deaths have been reported from CE.

Transmission

PPVO is found in skin lesions and scabs of infected animals and is transmitted by direct or indirect contact through cuts and abrasions. People acquire the infection from contact with infected animals/carcasses or fomites. Sheep can be carriers of PPVO and the virus can remain viable on wool and hides for approximately 1 month after lesions have healed. PPVO is very stable in the environment and has been recovered from dried lesions after 12 years. Nursing lambs can transmit the virus to their dam. There is no transmission of the virus to cattle. Human-to-human transmission does not occur.

Pathogenesis

CE is primarily a disease involving the skin with lesions appearing as papules, vesicles, and then pustules. Occasionally the virus is found in the lymph nodes. The epidermis may show marked hyperplasia. Necrosis of the epidermis with ulceration occurs in the center of the lesion that eventually sloughs. The viral infection causes intranuclear and intracytoplasmic inclusion bodies in keratinocytes and the superficial layers of the epidermis undergo degenerative changes. A dense inflammatory infiltrate (plasma cells, macrophages, histiocytes, and lymphocytes) is also observed. Microscopically the lesions are sharply delineated. In lambs, secondary infections with Staphylococcus bacteria are common.

Clinical Signs in Animals

CE occurs in sheep, goats, alpacas, camels, reindeer, musk oxen, bighorn sheep, deer, pronghorn antelope, and wapitis. Rare cases of dogs being infected after eating infected carcasses have been reported. Within 2 to 3 days of contacting the virus, the first clinical signs of CE are papules, pustules, and vesicles on the lips, nares, ears, eyelids, and sometimes feet of infected animals (Figure 7-33). Lesions may rarely be found in the esophagus, stomach, intestines, or respiratory tract. Teat and udder lesions can be found in dams that have acquired the virus from their nursing lambs. In time the pustules break and raised brown scabs form over these areas. If a number of pustules rupture close to each other, large scabs may result. These scabs are friable and bleed easily. CE lesions are painful and if found in the mouth may lead to anorexia and starvation, especially in lambs who refuse to nurse. Lambs may also be unable to nurse from ewes with udder or teat lesions because the dam will not let them nurse as a result of the pain. Mortality in lambs may be high as a result of malnutrition. Secondary bacterial infections may occur in the areas of the lesions. If there is no further infection of the lesions, CE lesions will heal in 1 to 4 weeks. Animals that contact the disease typically develop strong immunity and do not become reinfected for at least 1 year.

[FIGURE 7-33 OMITTED]

Clinical Signs in Humans

In people, CE typically appears as a single skin lesion (commonly as a small papule on the dorsum of the index finger) or a few lesions. The lesion is small, firm, and red that in time develops from a papule into a hemorrhagic pustule. Pustules may contain a central crust. In later stages, the lesion develops into a nodule containing fluid or may be covered by a thin crust. In time this lesion becomes covered by a thick crust. Low-grade fever and lymphadenopathy may occur with CE, which usually subsides within 3 to 4 days. In immunocompromised people, large lesions may develop. CE goes through six clinical stages in people with each stage lasting about 1 week.

* Stage 1 (maculopapular)--A red elevated lesion

* Stage 2 (targetoid)--A bulla with a red center, a white middle ring, and a red periphery

* Stage 3 (acute)--A weeping nodule

* Stage 4 (regenerative)--A firm nodule covered by a thin crust through which black dots are seen

* Stage 5 (papillomatous)--Small papillomas appearing over the surface

* Stage 6 (regressive)--A thick crust covering the resolving elevation

Diagnosis in Animals

Animals are typically diagnosed with CE based on clinical signs. Definitive diagnosis is confirmed by electron microscopy of the scabs (collected early in the disease). Other tests available include virus isolation, PCR, and serologic methods such as serum neutralization, agar gel immunodiffusion, complement fixation, agglutination, and ELISA tests.

Diagnosis in Humans

CE is diagnosed in people by electron microscopy with negative staining of the crust, a small biopsy, or fluid from the lesion. Viral isolation, PCR, RT-PCR, and serologic methods are also available.

Treatment in Animals

There is no specific treatment for CE. Supportive treatment such as antibiotics to prevent secondary bacterial infection, fly repellents to prevent maggots, and tube feeding for nutritional support may be used. If infected animals are kept clean, CE is self-limiting in 1 to 4 weeks without treatment.

Treatment in Humans

There is no specific treatment for CE. Supportive treatment with moist dressings, antiseptics, and antibiotics may be warranted. Large lesions in immunocompromised people may be removed by surgery, curettage, or electrocautery. Cryotherapy may be used to speed the recovery of CE in people.

Management and Control in Animals

The best preventative measure in animals is vaccination. A live virus vaccine should be used on farms where infections have occurred in the past. Recently vaccinated animals pose an increased risk of disease transmission to humans and other animals; therefore, recently vaccinated animals should be isolated from people and unvaccinated animals. Outbreaks have occurred in vaccinated animals. Isolation of infected animals may prevent disease spread on a farm; however, once the virus has entered a flock or herd it is difficult to eradicate.

Management and Control in Humans

People with skin cuts or abrasions should avoid infected animals and their wool/hides. Gloves should be worn if vaccinating animals for CE and contact with these animals should be temporarily avoided because the live vaccine may cause viral shedding.

Summary

Contagious ecthyma (CE) is a highly contagious, acute viral disease of sheep, goats, and wild ungulates. CE is caused by the contagious ecthyma virus in the Poxviridae family and Parapoxvirus genus. CE is found worldwide in countries that raise sheep. In the United States CE occurs most often in the Western states. CE virus is found in skin lesions and scabs of infected animals and is transmitted by direct or indirect contact through cuts and abrasions. The first clinical signs of CE are papules, pustules, and vesicles on the lips, nares, ears, eyelids, and sometimes feet of infected animals. Teat and udder lesions can be found in dams that have acquired the virus from their nursing lambs. In time the pustules break and raised brown scabs form over these areas. CE lesions are painful. CE lesions will heal in 1 to 4 weeks if not secondarily infected. In people, CE typically appears as a single skin lesion or a few lesions. The lesion is small, firm, and red that in time develops from a papule into a hemorrhagic pustule. In later stages, the lesion develops into a nodule containing fluid or may be covered by a thin crust. In time this lesion becomes covered by a thick crust. Low-grade fever and lymphadenopathy may occur with CE. Animals are typically diagnosed with CE based on clinical signs. Definitive diagnosis in animals and people is confirmed by electron microscopy of the scabs. Other tests available include virus isolation, PCR, and serologic methods such as serum neutralization, agar gel immunodiffusion, complement fixation, agglutination, and ELISA tests. There is no specific treatment for CE. Supportive treatment such as antibiotics to prevent secondary bacterial infection, fly repellents to prevent maggots, and tube feeding for nutritional support may be used in animals. Supportive treatment with moist dressings, antiseptics, and antibiotics may be warranted in people. The best preventative measure in animals is vaccination. Recently vaccinated animals pose an increased risk of disease transmission to humans and other animals; therefore, recently vaccinated animals should be isolated from people and unvaccinated animals. Isolation of infected animals may prevent disease spread on a farm; however, once the virus has entered a flock or herd it is difficult to eradicate. People with skin cuts or abrasions should avoid infected animals and their wool/hides. Gloves should be worn if vaccinating animals for CE.

Poxvirus Infection

Overview

Poxviruses produce eruptive skin pustules called pox, a term derived from the French poque meaning pouch or little pocket in the skin. Pox lesions leave small, depressed scars upon healing, which are called pockmarks. The best known poxvirus is variola virus, the agent that causes smallpox. Variola is Latin for smallpox and was used to describe a variety of mottled rashes as early as the 6th century. The first recorded cases of smallpox were in ancient Egypt on the mummy of Ramses V. The Roman Empire lost more than one-third of its subjects during a 15-year epidemic that began in A.D. 165. Crusaders brought smallpox back with them from the Holy Land. Variola became endemic in India in the first millennium B.C. and spread to Asia and, ultimately, to Europe in the 8th century. Hernando Cortez carried smallpox to the New World in 1520 where it killed many people in the Aztec and Inca empires. Smallpox was differentiated from other diseases (such as syphilis, which was known as the large pox) in the 10th century by Persian physician Abu Bakr Muhammed Ibn Zalariya. In America, smallpox allowed the Europeans to eradicate indigenous people because they had developed immunity to it and the natives had not. Pocahontas died of smallpox in 1617 after visiting London and epidemics in Europe in 1600 to 1700 killed royalty such as Queen Mary II of England (1694), Emperor Joseph I of Austria (1711), and King Louis XV of France (1774). In 1714 a Greek physician named Emanuel Timoni described how he prevented smallpox during an epidemic by embedding a knife in an infected person's rash and then scratching a healthy person with the blade. By 1717 this method of immunization was used in an outbreak in Boston in which 6,000 people contracted smallpox (900 died), but of the 287 people who were vaccinated only 6 died. Smallpox was responsible for at least 130,000 American deaths during the Revolutionary War because vaccination had been declared illegal. In 1796, Edward Jenner, an English doctor, noticed that milkmaids who contracted cowpox while milking infected cows were immune to smallpox. Jenner injected fluid from a cowpox pustule into 8-year-old James Phipps who did not contract smallpox. Vaccination did not catch on for a while (Abraham Lincoln contracted smallpox several hours after delivering the Gettysburg Address); however, by the 1950s vaccination of schoolchildren for smallpox eradicated the disease from the United States. In 1975 the last case of smallpox caused by wild variola major was in a 3-year-old Bangladeshi girl (last case in Asia) and the last case of smallpox caused by wild variola minor was in a 23-year-old Somalian in December 1977. In December 1979 the world was declared free of smallpox (certified by WHO in 1980) except for that found in research labs.
Smallpox was the most destructive
disease in history and the first to be
eradicated from nature in 1979.


There are a variety of poxviruses that infect animals and these must be ruled out as a differential diagnosis when the smallpox virus was found in nature. There is also concern that these animal poxviruses can cause an epidemic in people who are no longer protected from the smallpox vaccine or naturally occurring smallpox immunity.

Causative Agent

The poxviruses that cause diseases similar to smallpox are in the Orthopoxvirus genus and Poxviridae family. Orthopoxviruses are large (can be seen by light microscopy) and have a rectangular shape. Orthopoxviruses are large, enveloped, double-stranded DNA viruses that have an external surface ridged in parallel rows. These virus particles are extremely complex containing many proteins (more than 100). The outer surface is composed of lipid and protein, which surrounds the biconcave core. The core is composed of a tightly compressed nucleoprotein. The extracellular virus has two envelopes, whereas the intracellular virus has only one envelope. The orthopoxviruses cause disease in animals and people such as smallpox (variola), monkeypox, vaccinia, and cowpox viruses.

There are other poxviruses that cause disease in animals, but are not believed to be zoonotic. These poxviruses include the following genera and examples: Avipoxvirus (fowlpox); Capripoxvirus (sheep pox, goatpox, and bovine lumpy skin disease); Suipoxvirus (swinepox); and Parapoxvirus (pseudocowpox).

Epizootiology and Public Health Significance

Animal poxvirus infections occur worldwide and cause sporadic disease in people (rarely produce epidemics). Smallpox was eradicated from the world as of 1979 after a $330 million 10-year campaign against smallpox was completed. Smallpox eradication was first proposed by the Soviet Union in 1958. Smallpox has a mortality rate of approximately 30% in populations without immunity and is a concern of governments in regards to bioterrorism activity. In 1999, the WHO recommended that all existing laboratory stock of smallpox virus be destroyed by the end of 2002, but the bioterrorism acts of 2001 stopped this destruction. The last smallpox viruses are stored frozen in liquid nitrogen at the CDC in Atlanta and the Center for Research for Virology and Biotechnology in Koltsovo, Russia.
Chickenpox is a herpesvirus, not a
poxvirus.


[FIGURE 7-34 OMITTED]

Monkeypox infection poses some risk to people in Africa where the disease is seen mainly in children who have ingested infected monkey meat. The cross protection to monkeypox offered by smallpox vaccine is decreasing as a result of the cessation of smallpox vaccination in the 1970s. Case fatality rates for people from monkeypox in Africa range from 1% to 10% (mainly in children). An outbreak of monkeypox occurred in 2003 in the United States from exposure to infected prairie dogs (Figure 7-34).

The other zoonotic poxviruses rarely occur and do not pose as great a threat to human health as smallpox (nonzoonotic) and monkeypox.

Transmission

Transmission of most animal poxvirus to humans occurs by direct or indirect contact of nonintact skin or wounds with lesions of animal pox. Monkeypox can be transmitted by bite, aerosols, ingestion of infected meat, or direct contact with lesions. Rarely, human-to-human transmission of animal poxviruses has occurred. Smallpox is transmitted person-to-person by aerosol.

Pathogenesis

Pathogenesis varies with the poxvirus as described:

* Smallpox infection begins by inhalation of virus and has an incubation period of 10 to 14 days. The virus replicates locally, spreads to the regional lymph nodes, and an asymptomatic viremia is observed by day 3 or 4 of the infection. The virus then spreads to the bone marrow and spleen. A secondary viremic period begins on approximately day 8 and is associated with symptoms of fever and toxicity. The virus in leukocytes localizes in the blood vessels of the dermis and the characteristic rash of smallpox follows. Papules appear on the cheek and pharyngeal mucosa and on the face and extremities before progression to the trunk. Over several days, these papules form vesicles then slowly form pustules. Approximately 8 days after initial infection, the pustules rupture and scabs form. In time the smallpox lesions heal; however, they lead to significant scarring.

* Other poxviruses are introduced by cutaneous inoculation and replicate at the site of inoculation, leading to the formation of local red papules. These papules form vesicles then pustules, rupture, scar, and heal over 10 to 14 days. Poxvirus may also spread to regional lymph nodes, which become tender and produce fever. Other poxviruses generally follow the same pattern of evolution, with primarily localized disease.

* Unlike the other animal poxviruses, monkeypox infection leads to a clinical syndrome similar to smallpox. Infection is usually caused by invasion through broken skin and in most cases remains localized. Human monkeypox is acquired by contact or by airborne transmission to the respiratory mucosa. Initial viremia during the incubation period spreads infection to internal organs; a second viremia then spreads the virus to the skin.

Clinical Signs in Animals

There are a variety of poxviruses that infect a variety of animals (Figure 7-35). Zoonotic poxviruses are summarized in Table 7-15. Nonzoonotic poxviruses in animals include variola virus (only infects humans), volepox, ectromelia virus (rodents), raccoonpox, skunkpox, and taterapox (gerbils) and are not covered.

[FIGURE 7-35 OMITTED]

Clinical Signs in Humans

Smallpox in people is not zoonotic and presents in two clinical forms, variola major (25% to 30% fatality rate with signs of shock, toxemia, and intravascular coagulation) and a similar but milder disease known as variola minor (less than 1% fatality rate). Clinical signs include fever followed by the slow development of a papular rash typically on the face and extremities that then spreads to the trunk. The rash evolves rapidly into vesicles, followed by pustules, scabs, and healing.

Zoonotic poxvirus infections include the following:

* Monkeypox infection can produce a disease similar to variola minor that clinically cannot be distinguished from smallpox (Figure 7-36). Cases of monkeypox infection generally occur in villages in tropical regions of western and central Africa, but an outbreak occurred in 2003 in the midwestern United States from exposure to infected prairie dogs. During the 2003 outbreak, 71 people were infected with one person becoming severely ill after developing encephalitis.

* Cowpox infection causes a localized pustular skin lesion on hands, arms, and face. A febrile lymphangitis, conjunctivitis, and meningoencephalitis are rarely seen.

* Buffalopox, camelpox, and elephantpox produce a localized nodular lesion that is self-limiting.

[FIGURE 7-36 OMITTED]

Diagnosis in Animals

Poxvirus infections in animals may be suspected in animals with pustular lesions. Definitive diagnosis is done via histopathology, virus isolation, PCR, and ELISA tests.

Diagnosis in Humans

Most poxvirus infections can be recognized clinically with definitive diagnosis consisting of electron microscopy, virus isolation, PCR, and serologic tests such as hemagglutination inhibition, complement fixation, and ELISA tests.

Treatment in Animals

Animals are typically not treated for poxvirus infections. Antiretroviral drugs have been used in experimental animals with monkeypox virus. During the 2003 outbreak of monkeypox in the midwestern United States, the CDC recommended that all suspect animals be euthanized to prevent disease spread.

Treatment in Humans

Treatment of poxvirus infections in people is supportive. Cidofovir, an antiretroviral drug, has been used in animal studies as a possible treatment of monkeypox in humans.

Management and Control in Animals

The best preventative measure in animals is vaccination. The standard smallpox vaccine protects monkeys against monkeypox. An attenuated smallpox vaccine protects camels against camelpox. There is a vaccine for elephantpox that is a live attenuated vaccine. Vaccination for cowpox, feline cowpox, buffalopox, and horsepox is not practiced. Quarantine of infected animals or isolation of animals new to a facility can also decrease the outbreak of poxvirus among animals.
Eczema is a risk factor for vaccinia
infection.


Management and Control in Humans

All Orthopoxviruses are immunologically related; therefore, vaccination for one orthopoxvirus protects against the rest. Smallpox vaccination may offer protection against animal poxvirus infection. The CDC currently recommends smallpox vaccination only to people exposed to monkeypox. People who have contact with animals should protect skin cuts or abrasion from having direct contact with infected or suspect animals. Aerosol protection is recommended for people handling nonhuman primates.

Summary

Poxviruses produce eruptive skin pustules called pox that leaves small, depressed scars upon healing. The best known poxvirus is variola virus, the agent that causes smallpox. The poxviruses that cause diseases similar to smallpox are in the Orthopoxvirus genus and Poxviridae family. Animal poxvirus infections occur worldwide and cause sporadic disease in people. Transmission of most animal pox virus to humans occurs by direct or indirect contact of injured skin or wounds with lesions of animal pox. Monkeypox can be transmitted by bite, aerosols, ingestion of infected meat, or direct contact with lesions. There are a variety of poxviruses that infect a variety of animals that typically produce pustular lesions. Zoonotic poxvirus infections include monkeypox, cowpox, buffalopox, feline cowpox, horsepox, camelpox, and elephantpox. Poxvirus infections in animals may be suspected in animals with pustular lesions. Definitive diagnosis is done via histopathology, virus isolation, PCR, and ELISA tests. Most poxvirus infections in people can be recognized clinically with definitive diagnosis consisting of electron microscopy, virus isolation, PCR, and serologic tests such as hemagglutination inhibition, complement fixation, and ELISA tests. Animals are typically not treated for poxvirus infections. Treatment of poxvirus infections in people is supportive. The best preventive measure in animals is vaccination (if available for that animal species). Quarantine of infected animals or isolation of animals new to a facility can also decrease the outbreak of poxvirus among animals. Smallpox vaccination in people may offer protection against animal poxvirus infection. People who have contact with animals should protect skin cuts or abrasion from having direct contact with infected or suspect animals. Aerosol protection is recommended for people handling nonhuman primates.

REOVIRUSES

Overview

The Reoviridae, nonenveloped double-stranded RNA viruses, are a family of viruses that affect the gastrointestinal system and the respiratory system. The Reoviridae family began in 1959 when Albert Sabin reclassified an echovirus group (echo is an acronym for enteric cytopathic human orphan), a group of viruses not known to cause any human disease. The new viral family was called reo, an acronym for respiratory enteric orphan (orphan viruses are viruses not associated with any known disease). Although Reoviridae have since been identified with specific diseases, the original name is still currently used. The family Reoviridae is divided into nine genera with only four (Orthoreovirus, Coltivirus, Rotavirus, and Orbivirus) infecting humans and animals. Four other genera infect only plants and insects, and the last one only infects fish.

The genus Coltivirus, named for Colorado tick fever (the major disease in this group), contains two known zoonotic viruses, Colorado tick fever virus and Eyach virus (two other viruses in this group that may be zoonotic are Sunday canyon virus and Banna virus). Colorado tick fever is an arbovirus found in the Rocky Mountains of the United States and Canada. Its vector is Dermacentor andersoni and the disease in humans is characterized by sudden fever, muscle pain, leukopenia, and retroorbital eye pain. Eyach virus is found in Europe and is a tick-borne disease causing encephalitis and polyneuritis.

The genus Orbivirus was named for the ring-shaped capsomers making up the inner capsid (orbi is Latin for ring) and contains Kemerovo virus (an arbovirus transmitted by ticks causing febrile illness in Siberia), Orungo virus (a mosquito-borne virus that causes febrile illness in Africa), Lebombo virus (a rare, possibly mosquito-borne virus that causes febrile illness in Nigeria), and Changuinola virus (a fly transmitted virus that causes febrile illness in Panama).

The genus Orthoreovirus was named for the straight genome (ortho is Latin for straight) and does not cause significant disease in humans, but can infect a variety of mammals. Bluetongue is an example of a disease caused by an Orthoeovirus that is transmitted by the insect vector Culicoides varripennis and can infect cattle sheep, goats, and wild ruminants.

The genus Rotavirus was named for the wheel-like appearance (rota is Latin for wheel) and was first isolated from infant diarrhea by Stanley, Dorman, and Ponsford in 1951; however, it was not until 1973 when it was identified as the cause of gastroenteritis. Rotaviruses are found worldwide and occur in infants and young children causing fever, vomiting, diarrhea, and occasionally dehydration. Rotaviruses are not believed to be zoonotic.

Causative Agent

Viruses in the Reoviridae family have a double-stranded RNA, which is unlike any other RNA virus (Figure 7-37). This genome is linear and segmented with the number of segments varying with the genera of the particular virus (Orthoreovirus and Orbivirus have 10 segments, Rotavirus has 11 segments, and Coltivirus has 12 segments). Replication occurs in the cytoplasm within a nearly intact virion particle (in most other viral families, the virion disassembles and uncoats completely before it replicates). Reoviridae viruses are nonenveloped, spherical in appearance, and the capsid shape is icosahedral with two concentric capsid shells. They form distinctive inclusions that stain with eosin. Reoviruses are heat stable, stable through a wide pH range, and are stable in aerosols, particularly when the relative humidity is high. Reoviruses can be inactivated by 95% ethanol, phenol, and chlorine.

[FIGURE 7-37 OMITTED]

Orthoreoviruses are ubiquitous in nature and cause many inapparent infections based on the fact that most people have serum antibodies to orthoreoviruses by early adulthood. They have an inner protein shell surrounded by an outer protein shell. Reoviruses replicate in a large number of tissue culture systems of both primate and other animal origin and easily cause infection in laboratory animals making them good viruses for laboratory studies.

There are more than 100 serotypes of Orbiviruses, most infecting insects, and many transmitted by insects to vertebrates. Animal diseases caused by Orbiviruses include bluetongue virus of sheep and African horse sickness virus. Antibodies are found in many vertebrates, including humans.

Coltiviruses resemble the Orbiviruses in size and include such viruses as Colorado tick fever virus, Salmon River virus (Idaho), Eyach virus (in Europe), isolate S6-14-03 (California), Banna virus, Beijing virus, and Gansu virus (China). Colorado tick fever is the most common arboviral disease of humans in the United States (reported from at least 11 Western states in the United States and from Alberta and British Columbia in Canada).
Viruses in the Reoviridae family are also
called diplornaviruses (diplo is Greek
for double) because of their double-stranded
RNA genomes.


Rotavirus causes a large portion of gastroenteritis cases in children aged 6 months to 2 years. Rotavirus particles have a double-stranded RNA genome enclosed in a double-shelled capsid. Rotavirus has been found on all continents since its discovery in 1973. The transmission of rotavirus infections is fecal-oral with little evidence of airborne transmission.

The Reoviridae are summarized in Table 7-16.

Colorado Tick Fever

Overview

Colorado tick fever, also known as Colorado fever, is a nonfatal, tick-borne viral infection seen in the Rocky Mountains. Reports of mountain fever were first seen in the mid-19th century in settlers in the Rocky Mountains. Mountain fever probably included many different infectious diseases with a mild form of fever endemic to the area most likely being Colorado tick fever (CTF). William Clark of Lewis and Clark fame may have contracted CTF in July 1805 while traveling through the western United States. In 1930, Becker associated the mild form of mountain fever with exposure to the Rocky Mountain wood tick (Dermacentor andersoni) and named the disease Colorado tick fever. CTF was more thoroughly described by Topping in 1940 and the viral cause of CTF was discovered in both ticks and people by Florio in 1945. CTF is typically a relatively mild disease producing fever, headache, joint pain, and muscle pain in the spring and early summer months in endemic areas. There are many mammals that have been found to be naturally infected with CTF virus including hibernating animals that may help the virus survive winter and initiate a new cycle in spring.

Causative Agent

Colorado tick fever is caused by a virus in the family Reovirdiae in the genus Coltivirus. Reoviruses are nonenveloped, double-stranded RNA viruses with icosahedral symmetry and three capsid layers. Most Coltivirus proteins have yet to be characterized. Historically, Coltiviruses have been divided into subgroup A (North American and European species) and subgroup B (Asian species). Currently, subgroup A is known as the Coltivirus genus and subgroup B is separated into the Seadornavirus genus. The genus Coltivirus contains only CTF virus, California hare coltivirus, Eyach virus (found in Central Europe), and Salmon River virus.

Epizootiology and Public Health Significance

CTF is seen where its principal tick vector Dermacentor andersoni is found (Rocky Mountains including the western provinces of Canada). CTF is found in California, Colorado, Idaho, Montana, Nevada, Oregon, Utah, Washington, Wyoming, British Columbia, and Alberta. There is a seasonal occurrence of CTF with infections occurring mainly in April, May, and June, when adult ticks are abundant.

CTF causes four human cases of disease per 100,000 people with 50% of infected people developing clinical signs. The infection rate is more prevalent in Colorado where 15% of people who spend time outdoors are seropositive for the virus. Most western states include CTF on their reportable disease list; however, CTF is not a nationally reportable disease in the United States. Surveillance data is limited, but is it believed that there are approximately 200 case reports annually. Since the disease is usually mild and self-limiting control measures are not emphasized (however, tick control for other diseases is emphasized).

Transmission

CTF virus is transmitted mainly by the Ixodes (hard-shelled) tick Dermacentor andersoni. De. andersoni is found at elevations between 1,500 to 3,000 meters (greater than 4,000 feet). CTF virus is maintained in nature in a cycle involving ticks and a vertebrate reservoir in rodents and small mammals. The virus overwinters in nymph stage of ticks, which will feed on and infect small mammals in spring. Important reservoirs are ground squirrels, western chipmunks, wood rats, and deer mice. As the animals become viremic, they in turn infect larval ticks. The larvae metamorphose during the summer and they overwinter as infected nymphs. Ticks do not transmit virus to humans until reaching the adult stage, which may be 1 or 2 years after infection.
CTF virus can live in red blood cells for
the life of the cell (120 days).


Human-to-human transmission has occurred by blood transfusion.

Pathogenesis

CTF virus is introduced into an animal or human by the bite of a blood sucking tick. For approximately 2 weeks free virus can be isolated from blood. Virus then travels to the regional lymph nodes and eventually gets to the bone marrow where it replicates in bone marrow cells. In the bone marrow the virus stops the maturation of the neutrophils, eosinophils, and basophils and sometimes thrombocytes. Erythrocytes are infected with CTF virus as erythroblasts and are later detected in large numbers in erythrocytes in the peripheral blood. The virus is found only briefly in serum. Antibodies can be detected about 2 weeks after the onset of clinical signs and virus can be isolated from peripheral blood cells for up to 6 weeks. In less than 15% of infected children younger than 10 years of age, CTF virus invades the CNS and causes encephalitis.

Clinical Signs in Animals

CTF virus is not known to cause illness in mammalian species (they serve as amplifying hosts), although disease resembling human disease has been produced experimentally in laboratory mice, hamsters, Guinea pigs, and rhesus monkeys. Infection does not appear to affect survival of the Dermacentor andersonii tick.

Clinical Signs in Humans

The incubation period for CTF in people is 1 to 14 days. CTF in people appears abruptly, with initial clinical signs of high fever, chills, joint and muscle pains, severe headache, ocular pain, nausea, and occasional vomiting persisting for a few days. A transitory rash is seen in 5% to 12% of patients. In about 50% of people there is biphasic illness, in which acute symptoms last for several days, followed by fever remission, followed by a relapse lasting 2 to 3 days. This biphasic fever is also known as saddleback fever. A small proportion of people have more severe illness, including anorexia, continuing fatigue, and convalescence for several more weeks. CTF is typically more severe in children, who may have hemorrhagic manifestations such as DIC and gastrointestinal bleeding. CNS involvement (headache, neck stiffness, and photophobia) has been seen in severely affected children.

Diagnosis in Animals

Diagnosis of CTF in animals is not done clinically, but surveillance of disease can be done by virus isolation and neutralizing antibody tests.

Diagnosis in Humans

CTF can be diagnosed in people by virus isolation (from blood 2 to 4 weeks after infection) or serologic tests such as IgM capture ELISA, immunofluorescent assay, plaque reduction neutralization, and complement fixation tests. Antibodies to CTF virus are frequently seen in people who frequent endemic areas; therefore, a single elevated IgG titer does not indicate acute infection. RT-PCR can be used for diagnosis before antibodies appear.

Treatment in Animals

Animals are not treated for CTF.

Treatment in Humans

There is no specific treatment for CTF. Antipyretics and drugs to help control secondary infection may be used in cases of CTF.

Management and Control in Animals

Tick control may help decrease the level of viremia in small mammals, but a control program has not been established specifically for CTF.

Management and Control in Humans

Inactivated and modified live virus vaccine are available for CTF, but have not been widely used as a result of the mildness of disease produced by the CTF virus. Tick control will help decrease the spread of virus from ticks to animals and people. Recovered patients should not donate blood for a minimum of 6 months after recovery.

Summary

Colorado tick fever (CTF) is a nonfatal, tick-borne viral infection seen in the Rocky Mountains. CTF is caused by Colorado tick fever virus in the family Reovirdiae in the genus Coltivirus. CTF is seen where its principal tick vector De. andersoni is found (Rocky Mountains including the western provinces of Canada). There is a seasonal occurrence of CTF with infections occurring mainly in April, May, and June, when adult ticks are abundant. CTF virus is maintained in nature in a cycle involving ticks and a vertebrate reservoir in rodents and small mammals. Human-to-human transmission has occurred by blood transfusion. CTF virus is not known to cause illness in mammalian species (they serve as amplifying hosts). CTF in people appears abruptly, with initial clinical signs of high fever, chills, joint and muscle pains, severe headache, ocular pain, nausea, and occasional vomiting persisting for a few days. In about 50% of people there is biphasic illness, in which acute symptoms last for several days, followed by fever remission, followed by a relapse lasting 2 to 3 days. CTF is typically more severe in children, who may have hemorrhagic manifestations such as DIC, gastrointestinal bleeding, and CNS involvement. Diagnosis of CTF in animals is not done clinically, but surveillance of disease can be done by virus isolation and neutralizing antibody tests. CTF can be diagnosed in people by virus isolation (from blood, 2 to 4 weeks after infection) or serologic tests such as IgM capture ELISA, immunofluorescent assay, plaque reduction neutralization, and complement fixation tests. RT-PCR can be used for diagnosis before antibodies appear. Animals are not treated for CTF. There is no specific treatment for CTF in people. Tick control may help decrease the level of viremia in small mammals and help decrease the spread of virus from ticks to animals and people. Inactivated and modified live virus vaccine are available for CTF in people, but have not been widely used as a result of the mildness of disease produced by the CTF virus. Recovered patients should not donate blood for a minimum of 6 months after recovery.
Table 7-12 Less Common Zoonotic Paramyxoviruses

                                          Predominant
Paramyxovirus      Disease                Signs in People

Hendra virus       Hendra virus           Acute dyspnea,
                   disease                hemorrhagic
                   First discovered       disorders, and
                   in 1994 in horses      neurologic tissue
                   in Brisbane,           necrosis
                   Australia (Hendra
                   is a suburb of
                   Brisbane)

Menangle virus     Menangle               Influenza-like
                   First discovered in    illness with a
                   a swine operation      macular rash; no
                   in Menangle near       fatalities reported
                   Sydney in New
                   South Wales,
                   Australia in 1997.

Tioman virus       Tioman virus           It is not proven
                   disease                that Tioman
                   First isolated on      virus can cause
                   Tioman island,         illness in humans
                   Malaysia in 2000       or animals; its
                   while trying           relationship
                   to discover the        to other
                   natural host of        disease-causing
                   Nipah virus            paramyxoviruses
                                          suggests a
                                          possibility that
                                          it may cause
                                          disease when
                                          it crosses the
                                          species barrier.

                   Animal Source
Paramyxovirus      and Clinical Signs     Transmission

Hendra virus       * Horses               * Close contact
                     develop                with infected
                     hemorrhagic            horses
                     fever and            * Horses contract
                     respiratory            disease
                     distress with          indirectly
                     high fatality          from fruit bats
                     rates                  (flying foxes
                   * Highly                 of the genus
                     pathogenic             Pteropus).
                     in pregnant            Flying foxes
                     mares                  stay in trees
                                            overnight and
                                            infectious
                                            excrement
                                            is shed onto
                                            pastures where
                                            horses can be
                                            exposed.

Menangle virus     * Pigs (typically      * Close
                     10 to 16               association
                     weeks old)             with infected
                     harbor active          pigs (especially
                     infection.             during
                   * Infected               necropsy
                     sows may               or birthing
                     abort, have            procedures)
                     mummified            * Pigs may
                     or autolysed           become
                     piglets, or they       infected
                     may be born            by flying
                     with skeletal or       foxes (genus
                     nervous system         Pteropus).
                     deformities.

Tioman virus       * Bats are             * Contact with
                     asymptomatic.          the urine
                                            of fruit bats
                                            (Pteropus
                                            hypo-
                                            melanus).

                   Geographic
Paramyxovirus      Distribution           Diagnosis

Hendra virus       Australia              Virus isolation in
                                          cell culture, RT-
                                          PCR, ELISA

Menangle virus     Australia (only        Virus
                   outbreak was           isolation, virus
                   in New South           neutralization,
                   Wales)                 ELISA

Tioman virus       Malaysia               Western blot

Paramyxovirus      Control

Hendra virus       Use barrier
                   protection
                   when handing
                   suspicious horses
                   (gloves, goggles,
                   masks with
                   respirators, etc.);
                   avoid contact with
                   flying foxes and
                   their excrement;
                   do not plant
                   flowering or
                   fruit trees near
                   farm buildings;
                   isolation of
                   affected animals.

Menangle virus     Use barrier
                   protection
                   when handling
                   suspicious pigs
                   (gloves, goggles,
                   masks with
                   respirators, etc.);
                   avoid contact with
                   flying foxes and
                   their excrement;
                   do not plant
                   flowering or
                   fruit trees near
                   farm buildings;
                   isolation of
                   affected animals.

Tioman virus       Avoid contact with
                   flying foxes.

Source: Kraus, Center for Food Security and Public Health,
Menangle, Iowa State University, 1/24/06.

Table 7-13 Vesicular Diseases in Animals

Disease                 Type of Virus    Major Species Affected

Foot-and-mouth          Picornavirus     Swine, cattle, sheep, goats,
disease                                  African buffaloes

Swine vesicular         Picornavirus     Swine
disease

Vesicular exanthema     Calicivirus      Swine, marine mammals
of swine

Vesicular stomatitis    Rhabdovirus      Horses, cattle, swine,
                                         wildlife, llamas, alpacas

Disease                 Transmission

Foot-and-mouth          Aerosol, contact, fomites
disease

Swine vesicular         Contact, fomites
disease

Vesicular exanthema     Contact, fomites
of swine

Vesicular stomatitis    Insects, direct contact

Table 7-14 Less Common Zoonotic Picornaviruses

                                        Predominant
Picornavirus    Disease                 Signs in People

Encephalo-      Encephalomyo-           Fever, severe
myocarditis     carditis                headaches,
virus           There are 4             vomiting,
                strains; originally     stiff neck, and
                isolated in 1940        hyperactive
                from a monkey           reflexes; rare
                EMC virus has the       in humans and
                ability to cause        not fatal
                interspecies
                infections
                and had led
                to numerous
                outbreaks
                in zoos in
                Australia and the
                United States.

                Animal Source and
Picornavirus    Clinical Signs          Transmission

Encephalo-      * Pigs (less than 2     * Virus is shed
myocarditis       months of age)          in feces and
virus             may die                 transmitted in
                * Nonhuman                contaminated
                  primates may die        food, water,
                  suddenly                and infected
                * Rodents are likely      cadavers.
                  reservoir hosts
                * Virus has been
                  isolated from
                  horses, cattle,
                  pheasants, and
                  mosquitoes.

                Geographic
Picornavirus    Distribution            Diagnosis

Encephalo-      Virus exists            Virus
myocarditis     worldwide, but          isolation, virus
virus           natural disease         neutralization,
                only seen               hemaggluti-
                in Europe.              nation, PCR

Picornavirus    Control

Encephalo-      Proper hygiene and
myocarditis     using caution when
virus           handling diseased
                animals

Table 7-15 Zoonotic Animal Orthopoxviruses and the Diseases They Cause

Virus                                Species Affected

Monkeypox virus                      New and Old World
Originated in Zaire in 1970-1971     monkeys; rodents (rats,
and was transmitted from monkeys     mice, squirrels, and prairie
to unvaccinated humans.              dogs); rabbits

Vaccinia virus                       Unknown
Vaccinia virus has been used to
immunize people against smallpox
and was the original virus
obtained from cattle; assumed to

Buffalopox virus                     Waterbuffalo and cattle
First characterized in 1971 in
India

Camelpox virus                       Camels
Seen in Africa and Asia
Most closely related to smallpox

Cowpox virus                         Cattle (also cats,
                                     anteaters, and rodents)

Feline cowpox                        Domestic and zoo cats
This virus is identical to           (lions, cheetahs, pumas,
cowpox virus and is believed         etc.)
to cause about 50% of cowpox
infections in people.

Horsepox                             Horses
Also known as grease-heal and
contagious pustular stomatitis

Elephantpox virus                    Circus or zoo elephants

Virus                                Clinical Signs in Animals

Monkeypox virus                      Nonhuman primates have
Originated in Zaire in 1970-1971     self-limiting rash and fever
and was transmitted from monkeys     (mortality may be seen in young
to unvaccinated humans.              monkeys); rodents and rabbits
                                     have fever, conjunctivits,
                                     nasal discharge, cough,
                                     lymphadenopathy, anorexia, and
                                     lethargy.

Vaccinia virus
Vaccinia virus has been used to
immunize people against smallpox
and was the original virus
obtained from cattle; assumed to

Buffalopox virus                     Buffalo and cattle develop skin
First characterized in 1971 in       eruptions
India

Camelpox virus                       Camels (especially young) develop
Seen in Africa and Asia              pustules around nares, lips, and
Most closely related to smallpox     hairless areas. Young camels have
                                     25% mortality rate

Cowpox virus                         Cattle develop nodules of the
                                     udder and teats; decrease in
                                     milk production may occur due
                                     to the soreness of affected
                                     teats or secondary bacterial
                                     infection.

Feline cowpox                        Felines develop chronic disease
This virus is identical to           with multiple skin lesions that
cowpox virus and is believed         present as papules, followed by
to cause about 50% of cowpox         vesicles, then pustules, and
infections in people.                finally scabs. Lesions are
                                     randomly distributed over the
                                     body.

Horsepox                             Horses develop papules, vesicles,
Also known as grease-heal and        and pustules on the skin of lips,
contagious pustular stomatitis       nares and oral mucous membranes.
                                     Other clinical signs include
                                     nasal discharge, fever, and
                                     salivation. "Leg" form has
                                     pustules on leg and lameness

Elephantpox virus                    Elephants develop fever,
                                     lameness, conjunctivitis, and
                                     pustules.

Virus                                Clinical Signs in People

Monkeypox virus                      Resembles smallpox and
Originated in Zaire in 1970-1971     may be fatal
and was transmitted from monkeys
to unvaccinated humans.

Vaccinia virus                       Used for vaccination in
Vaccinia virus has been used to      humans; originally produced
immunize people against smallpox     nodular lesions but now
and was the original virus           appears to be hybrid strain
obtained from cattle; assumed to

Buffalopox virus                     Nodular lesions typically on
First characterized in 1971 in       hand or face
India

Camelpox virus                       Produces nodules on the
Seen in Africa and Asia              hands of camel drivers
Most closely related to smallpox

Cowpox virus                         Produces single lesion on
                                     hand or face of person in
                                     close contact with affected
                                     cattle

Feline cowpox                        Produces single lesion on
This virus is identical to           hand or face of person in
cowpox virus and is believed         close contact with affected
to cause about 50% of cowpox         felines
infections in people.

Horsepox                             Rare in humans
Also known as grease-heal and
contagious pustular stomatitis

Elephantpox virus                    Produces nodular lesions

Table 7-16 Various Types of Reoviruses and Their Properties

                                  Geographic
Virus Name        Genus           Distribution       Vector

Rotavirus         Rotavirus       Worldwide          None known

Orthoreoviruses   Orthoreovirus   Worldwide          None known,
                                                     possible
                                                     zoonotic

Colorado Tick     Coltivirus      Rocky Mountains,   Wood
Fever virus                       North America      tick--Dermacentor
                                                     andersoni

Sunday canyon     Coltivirus      North America      Tick
virus

Eyach             Coltivirus      Europe             Tick

Banna virus       Coltivirus      China              Not known

Orungo            Orbivirus       Africa             Mosquitoes

Lebombo           Orbivirus       Africa             Mosquitoes

Changuinola       Orbivirus       Panama             Phlebotomine fly

Kemerovo          Orbivirus       Russia (Siberia)   Ticks

Virus Name        Disease Signs               Transmission Route

Rotavirus         Gastroenteritis (infant)    Fecal-oral; possibly
                                              respiratory

Orthoreoviruses   Possible respiratory        Fecal-oral and
                  illness (mild)              respiratory

Colorado Tick     Febrile                     Arboviral; arthropod
Fever virus       illness--encephalitis,      vector
                  hemorrhagic fever

Sunday canyon     Febrile illness             Arboviral; arthropod
virus                                         vector

Eyach             Possibly encephalitis       Arboviral; arthropod
                                              vector

Banna virus       Febrile illness,            Vector
                  encephalitis

Orungo            Febrile illness             Arboviral; arthropod
                                              vector

Lebombo           Febrile illness             Arboviral; arthropod
                                              vector

Changuinola       Febrile illness             Arboviral; arthropod
                                              vector

Kemerovo          Febrile illness,            Arboviral; arthropod
                  encephalitis                vector

Modified from Loerke, C. www.stanford.edu
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Title Annotation:Part 3: PICORNAVIRUSES-REOVIRUSES
Author:Romich, Janet Amundson
Publication:Understanding Zoonotic Diseases
Article Type:Disease/Disorder overview
Geographic Code:1USA
Date:Jan 1, 2008
Words:12601
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