Tyzzer disease is an enterohepatic syndrome of a wide range of animals (see Tyzzer Disease) and is seen worldwide. Tyzzer disease was first described in mice in 1917. Several years later, it was reported in laboratory rabbits and then in other small laboratory mammals, including guinea pigs, hamsters, gerbils, and rats. It is a highly fatal disease of young foals. The disease is rare in other domestic animals, including dogs, cats, and calves. It has been reported in a variety of wildlife, including muskrats, cottontail rabbit, coyote, gray fox, lesser panda, snow leopard, raccoon, marsupials, and white-tailed deer.
The disease primarily affects young, well-nourished animals, especially those fed high-protein diets, during periods of stress. Some species appear resistant unless stressed or immunosuppressed, whereas others appear to be susceptible without immunosuppression. Dietary factors, including excessive nitrogenous diets fed to laboratory animals and to nursing mares, seemingly may cause immunosuppression and may predispose susceptible animals to the disease. Other immunosuppressive agents and drugs and some antibacterials, especially sulfonamides, may also predispose animals to the disease.
Under laboratory conditions, stress is created by immunosuppressive drugs or other factors that can be easily identified. With many experiments, stress may be involved as part of the protocol, and when the disease develops, it is devastating.
Etiology and Pathogenesis
The disease is caused by Clostridium piliforme, a motile, spore-forming, rod-shaped, flagellated, obligate, intracellular bacterium. It does not grow in cell-free media but can be cultured in the yolk sac of chick embryos or tissue culture cells. The vegetative phase is very labile; spores may survive in soiled bedding at room temperature for >1 yr and are resistant to heating up to 60°C for 30 min, or exposure to 70% ethanol, 3% cresol, 4% chlorhexidine, and 0.037% formaldehyde; however, they are sensitive to 0.4% peracetic acid, 0.015% sodium hypochlorite, 1% iodophor, and 5% phenol.
C piliforme appears to be common in the environment, but because it is difficult to culture, very little knowledge has been accumulated on the epidemiology, pathogenesis, and immunity. Infection most likely results from oral exposure to spores from the environment. The feces of infected and carrier animals are the primary source of spores that contaminate the environment.
C piliforme infections are often subclinical or asymptomatic but may be severe in many animal species. There may be differences in susceptibility within animal species. B lymphocytes, T lymphocytes, and natural killer cells may play a role in mediating strain susceptibility. Seroanalysis using monoclonal antibody-based competitive inhibition ELISA suggests that Tyzzer disease may be relatively common in horses, which are susceptible to at least two distinct strains.
Some isolates of C piliforme produce toxins, whereas others do not. The role of these toxins in the pathogenesis of infection is unknown, but the toxic isolates are generally more virulent than nontoxic isolates. The toxigenic strains appear more likely to induce hepatic lesions in mice, whereas the nontoxigenic strains do not.
The primary site of infection is the lower intestinal tract with subsequent dissemination via the blood or lymphatics to the liver and heart. The bacterium has an affinity for the epithelial and smooth muscle cells of the intestines, hepatocytes, and cardiac myocytes. Stress factors such as capture, overcrowding, shipping, and poor sanitation appear to be predisposing. Sulfonamide administration predisposes rabbits to the disease. Mortality is highest at weaning age in rabbits. The disease in foals occurs most often between 1 and 6 wk of age, with most cases occurring between 1 and 2 wk of age. In some species, the disease has been identified concurrently with other diseases, eg, feline infectious peritonitis in cats, distemper and mycotic pneumonia in dogs, and cryptosporidial and coronaviral enteritis in calves.
The disease in foals is more common during the spring when nursing mares are exposed to lush, high-protein pastures. The increase in the availability of nutrients from pasture forages and supplemental diets may encourage the overgrowth of C piliforme in the gut of nursing mares; this seemingly predisposes neonatal foals to the disease when they are exposed to massive numbers of the bacterium after consuming the feces of their dams soon after birth as a mechanism to establish their normal intestinal flora. The immature gut is likely more permeable to pathogens like C piliforme.
The disease in young foals primarily affects the liver, where it induces a massive multifocal necrosis and hepatitis, and foals die of acute liver failure. In contrast, in other animals, which generally are older when infected, the bacterium affects the intestinal tract and to a lesser extent the liver and heart.
Older foals up to 6 wk of age become more resistant to the disease as the gut becomes more mature and immune factors may be involved. The disease is not recognized in older foals and adults, but they carry the bacterium in their gut.
Immune factors appear to be involved with the disease in horses, because many adults have antibodies for C piliforme yet do not develop Tyzzer disease. Only young foals up to 6 wk old develop lesions. The disease is more common in foals when young nursing mares are introduced to a farm where the disease is endemic and is less common in suckling foals on older mares; this suggests that older mares are immune to the disease and may be secreting C piliforme antibodies in the colostrum that protects young foals.
The disease often affects apparently healthy, fast-growing foals without previously observed clinical signs. The incubation period in experimentally infected foals is 4–7 days after oral exposure to bacterial spores. Most foals are found in a coma or dead. Clinical signs, if seen, are of short duration, from a few hours to up to 2 days. Signs are variable but may include depression, anorexia, pyrexia, jaundice, diarrhea, and recumbency. Terminally, there are convulsions and coma. Clinical signs vary between animal species. Laboratory animals may be found dead at the start of an outbreak. As the disease progresses, animals may show depression, ruffled coat, and varying degrees of watery diarrhea.
Clinicopathologic tests are of little value in laboratory animals, because they die so rapidly. In foals, the serum enzymes sorbitol dehydrogenase, AST, alkaline phosphatase, lactate dehydrogenase, and γ-glutamyltransferase are increased. There is also hyperbilirubinemia, leukopenia, hemoconcentration, and terminally profound hypoglycemia.
Characteristic lesions are seen in the liver, myocardium, and intestinal tract. In the liver, white, gray, or yellowish foci of necrosis, 2 mm in diameter, are few to disseminated. The hepatic necrosis is most marked and disseminated in foals in which the multiple necrotic foci with slightly depressed hemorrhagic centers appear to infect almost every hepatic lobule. In addition, there is marked hepatomegaly, and the hepatic lymph nodes are edematous and hyperplastic. In rabbits, severe lesions develop in the intestines and heart. The terminal ileum, cecum, and proximal colon are diffusely reddened. Diffuse (“paint-brush”) hemorrhage is frequently seen on the serosa of the cecum. Patchy areas of mucosal necrosis are present in the cecum and colon, together with marked edema of the wall of the cecum. Mesenteric lymph nodes may be enlarged and edematous. White streaks in the myocardium may be present, especially near the apex. Intestinal and heart lesions are generally milder or absent in other animal species.
Microscopically, there are numerous widespread multifocal areas of necrosis and hepatitis. In foals, the hepatic lesions are more pronounced than in other animals. Often the necrotic foci are so numerous that two or more coalesce. The hepatocytes in the center of the necrotic foci are destroyed and replaced by a mixture of mononuclear cells, neutrophils, and red blood cells. The causative bacteria are found in a crisscross pattern in viable hepatocytes at the periphery of the necrotic foci. In the cecum and colon of rabbits, patchy areas of necrosis extend as deep as the muscularis externa with associated mucosal and submucosal infiltrates of neutrophils. Organisms may be found within the epithelium, muscularis mucosa, and muscularis externa of the affected intestine. When cardiac lesions are present, they consist of foci of fiber fragmentation, vacuolation, loss of cross-striations, and minimal inflammatory cell infiltration.
Serology of the blood and PCR assay of the feces of suspect infected animals may be used clinically to test for C piliforme. However, clinical signs in addition to the commonly available diagnostic methods must be interpreted together for a presumptive clinical diagnosis.
In postmortem specimens, a diagnosis is based on demonstration of organisms in tissue sections with special stains. C piliforme stains poorly with H&E and Gram stains. With Giemsa stain, the bacillus stains well in the liver and intestinal epithelium and in smears of infected organs but poorly in smooth muscles and cardiac muscle cells. The Warthin-Starry or Levaditi silver stains are preferable to other stains, because the bacillus stains well in the cytoplasm of all infected cells. In addition to special histochemical stains, the PCR assay can be used to detect C piliforme gene sequences in liver tissues from infected animals.
Treatment and Control
Little is known about the effectiveness of antibiotics for treatment. Some antibiotics are known to aggravate the disease. C piliforme is sensitive to tetracycline and partially sensitive to streptomycin, erythromycin, penicillin, and chlortetracycline. It is resistant to sulfonamides and chloramphenicol.
In neonatal foals, the disease seems to be nearly 100% fatal, although it is likely that older foals less severely affected may survive. Once the disease is present on a farm, it may be seen sporadically year after year. Animals suspected of being infected have been treated IV initially with 50% dextrose, followed by 10% dextrose, other fluid therapy, and antibiotics. Most foals respond dramatically to the dextrose therapy but relapse into a coma and die in a few hours. A few presumptive cases of Tyzzer disease in foals have been treated successfully by intensive administration of IV dextrose, sodium bicarbonate, potassium chloride, penicillin, and sulfamethoxazole-trimethoprim.
Because the disease in foals is sporadic and not highly contagious, specific preventive measures are usually not indicated. In areas where endospores are present in the environment, many foals may be exposed; however, only a few that are immunosuppressed become acutely affected. On premises where the disease is prevalent, overfeeding of mares, especially with high-protein diets seemingly predispose neonatal foals. Reducing the nitrogenous dietary compounds, including protein and nitrate in the diet that may induce immunosuppression in neonatal foals, may lessen the incidence of the disease. In general, factors that cause stress and immunosuppression should also be reduced. When the disease is seen in a colony of laboratory animals, treatment is not recommended because it prolongs the disease and possibly produces carrier animals. It is best to destroy all animals in the colony, decontaminate the environment, and restock with disease-free animals.
Last full review/revision October 2013 by Thomas W. Swerczek, DVM, PhD