13 Francisco A. Uzal, Federico Giannitti, John W. Finnie, and Jorge P. García Enterotoxemia caused by Clostridium perfringens type D, sometimes also called “overeating disease” or “pulpy kidney disease,” is one of the most prevalent clostridial diseases of sheep and goats worldwide. The disease occurs rarely in cattle, and a few poorly characterized cases have been described in other species. Because the so-called focal symmetrical encephalomalacia (FSE) is one of the lesions that may be seen in the sub-acute and chronic forms of type D enterotoxemia of sheep, this term was used in the past and it is still occasionally used to refer to these forms of the disease. However, it is not recommended as a name for type D enterotoxemia, since this term refers only to the pattern of brain damage in those forms of type D disease. The name “pulpy kidney disease” should also be abandoned, as it refers to a likely post-mortem change and not to a lesion of this disease. Type D enterotoxemia in sheep is a pure enterotoxemia, with no bacterial invasion of tissues, whereas in goats it may be a pure enterotoxemia, a localized enteric disease, or a combination of both. Although C. perfringens is acquired by the oral route and reaches the intestine, disease development in infected animals is dependent upon predisposing factors including individual intestinal environmental conditions that determine local toxin production. Therefore, type D enterotoxemia is considered a non-contagious disease, although it can occur in outbreaks under some specific circumstances. Because the disease is almost always fatal, it can result in significant economic losses for the livestock industry, particularly in unvaccinated flocks. C. perfringens type D produces two typing toxins, namely alpha (CPA) and epsilon (ETX), although most type D isolates may express several other toxins. However, the use of reverse genetic experiments in vitro and in vivo has demonstrated that ETX is the main virulence factor responsible for most and probably all clinical signs and lesions of C. perfringens type D disease in sheep and goats. ETX is the third most potent clostridial toxin, after botulinum and tetanus toxins. Because of its potency and potential as a biological weapon, this toxin was, until 2012, considered a class B select agent by the United States Department of Agriculture and the Center for Disease Control. A detailed description of all C. perfringens toxins is provided in Chapter 5. Whether there is host adaptation of type D strains to sheep, goats, and possibly cattle has not been determined, but if this is the case, it might explain the differences in the somewhat different nature of the disease among these species. Type D enterotoxemia occurs in most areas of sheep and goat production in the world. The disease affects lambs and goat kids older than 2 weeks in particular, but it can also affect adult sheep and goats. Infrequent, poorly documented cases may have occurred in lambs younger than 2 weeks. The most common predisposing factor for type D enterotoxemia in sheep and goats is sudden feeding of large amounts of grain or concentrate to unaccustomed animals; hence the synonym “overeating disease.” Under field conditions, grazing of abundant, lush pasture has also been associated with cases of type D enterotoxemia, mostly in sheep. However, the mechanism by which these nutritional factors induce the disease is incompletely understood. Although the majority of C. perfringens type D cells ingested are destroyed in the pre-stomachs and abomasum, the few organisms that reach the intestine proliferate and produce toxins when the intestinal environment is favorable. Traditionally, it was accepted that for type D enterotoxemia to occur, undigested starch in the small intestine was required. Starch would thus provide a suitable substrate for saccharolytic C. perfringens, allowing it to multiply and reach numbers that may approximate 109 organisms per gram of intestinal contents, with subsequent production of large amounts of ETX. Although this may be a predisposing factor, it has recently been demonstrated in vitro that the absence of glucose in a culture medium stimulates ETX production by C. perfringens type D. If this also occurs in vivo, it could be postulated that, while the presence of starch in the intestine stimulates the growth of C. perfringens type D, the absence of glucose stimulates ETX production. When ruminants have sudden and novel access to large amounts of starch-rich food, the ruminal microbiota requires several days or weeks to adapt, permitting substantial quantities of undigested starch to reach the intestine and providing a rich substrate for the proliferation of C. perfringens type D. Concomitantly, failure to digest starch would also result in a lack of glucose in the small intestine, stimulating ETX production. ETX is produced in the exponential phase of bacterial growth and secreted from the bacterial cytosol as a relatively inactive prototoxin, which becomes fully activated in the extracellular environment by the removal of N- and C- terminal peptides by the action of proteolytic digestive enzymes, including trypsin and chymotrypsin, although C. perfringens lambda toxin can also activate this prototoxin. In the intestine, activated ETX seems to increase mucosal permeability, thus facilitating its own absorption into the bloodstream. Once absorbed, this toxin is distributed to several internal organs, including the brain, lungs, liver, heart, and kidneys. In target organs, the toxin binds a yet-unidentified receptor on the luminal surface of vascular endothelial cells, which can be experimentally and transiently prevented, via competitive inhibition, by prior injection of epsilon prototoxin. ETX-induced microvascular endothelial damage leads to increased vascular permeability and resulting severe vasogenic edema. The generalized edema in the brain produces raised intracranial pressure and marked neurologic disturbance and, in the lungs and perhaps other organs, hypoxic injury. Following blood–brain barrier breakdown, some of the toxin enters the brain and may have a direct and damaging effect on neurons. In goats, the pathogenesis of the acute and sub-acute disease is believed to be similar to that in sheep, although intestinal lesions can also occur in the sub-acute form. Chronic disease in this species is confined to the colon and less commonly the small intestine, and is believed to be caused by local effects of ETX and perhaps other C. perfringens type D toxins. The disease in cattle seems to have a similar pathogenesis to that in sheep. The common occurrence of the disease in young, unvaccinated ruminants is related, at least in part, to the decline in maternally derived ETX-neutralizing antibodies. Type D enterotoxemia in lambs is generally acute, with animals dying after a short period of mainly neurologic and respiratory signs, including convulsions, tachypnea, and bawling. Some animals may survive longer and show tachypnea, ptyalism, hyperesthesia, a wide-based stance, head pressing, blindness, opisthotonos, and terminal convulsions or coma. Sudden death, characterized by animals being found dead without premonitory clinical signs, may also occur. Sub-acute or chronic cases are most commonly seen in older sheep or younger but vaccinated animals, probably due to the presence of some anti-ETX antibodies from vaccination that afford some level of protection or exposure to small amounts of toxin absorbed from the intestine. These forms of type D enterotoxemia are characterized by neurologic clinical signs, including blindness, ataxia, head pressing, and paraparesis. Diarrhea may occasionally be observed, but this is not a common clinical sign in ovine type D enterotoxemia. While C. perfringens type D ETX is usually incriminated in disease, a type D strain producing unusually high amounts of CPA was isolated from a lamb with hemolytic disease resembling “yellow lamb disease”, a form of enterotoxemia characterized by acute intravascular hemolysis, typically associated with CPA produced by C. perfringens type A (Chapter 8). Hyperglycemia, largely from rapid mobilization of hepatic glycogen, and marked glycosuria can be found in all forms of the disease, albeit inconsistently, and are useful diagnostically when present. However, these biochemical changes do not occur consistently, and a diagnosis of type D enterotoxemia is not precluded by the absence of hyperglycemia or glycosuria. Both kids and adult goats may be affected. As in sheep, acute, sub-acute, and chronic forms are recognized. The acute form of the disease is similar to that seen in lambs, and usually manifests as sudden death or acute neurologic and/or respiratory signs. It occurs more frequently in young, unvaccinated animals. The sub-acute form, which usually affects older goats, is characterized by diarrhea, which may be hemorrhagic, and severe abdominal discomfort, with or without neurologic or respiratory signs. Affected animals usually die within 2–4 days of the onset of clinical signs, but some may recover. The chronic form of the disease may persist for a few days or weeks and tends to occur in adult animals which have been vaccinated; animals may die or recover. This form of the disease presents as profuse, watery, and/or hemorrhagic diarrhea frequently containing mucus, abdominal discomfort, weakness, anorexia, weight loss, and agalactia in milking does. Hyperglycemia and glycosuria can occasionally occur in goats with any of the forms of type D disease. In the acute form of type D enterotoxemia in lambs, carcasses are usually well nourished. There may be evidence of diarrhea, although this is an unusual finding in sheep. Mild congestion and hemorrhage may sometimes be observed on the small intestinal mucosa, the small and large intestinal content may be moderately fluid, and the small intestine may be multifocally distended with gas, but no other gross changes are seen in the gastrointestinal tract. Pulmonary edema, with wide interlobar and interlobular septae (Figure 13.1) and a large amount of stable froth in the trachea and lower airways (Figure 13.2), is regularly found. Hydropericardium (Figure 13.3), hydrothorax, and ascites, with or without strands of fibrin, are characteristic, but not consistent, post-mortem findings in sheep. Due to their high protein concentration, these fluids tend to clot when the respective cavities are opened (Figure 13.3). Other gross changes include sub-endocardial and sub-epicardial hemorrhages, which are particularly marked in the left ventricle, serosal hemorrhages, and hepatic and splenic congestion. Figure 13.1 Pulmonary edema in a sheep with type D enterotoxemia. The interlobar and interlobular septae are diffusely expanded and filled by a clear fluid (edema). Reprinted with permission from Uzal et al. (2008) 20: 253–265.
Diseases Produced by Clostridium perfringens type D
Introduction
Etiology
Epidemiology and pathogenesis
Clinical signs
Sheep
Goats
Gross changes
Sheep
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