Pathogenesis: The epithelial cells over the upper two-thirds of the affected villi of the proximal small intestine are infected first in those species that suffer with severe diarrhea from rotavirus infection (Web Fig. 7-18). Sloughing of villous cells results in shortening and sometimes fusion of villi, if basement membranes are exposed (Fig. 7-123). Interestingly, besides causing a malabsorptive diarrhea, rotaviruses produce a secretory enterotoxin nonstructural protein (NSP4) that increases chloride secretion through a calcium-dependent mechanism. This toxin also activates the enteric nervous system and blocks the intestinal sodium/glucose cotransporter. All of these increase fluid and the rate of peristalsis in the intestinal lumen. Depending on the degree of enterocyte loss, recovery may be delayed or incomplete, depending on the amount of absorptive surface that is permanently lost. When death occurs, it is generally associated with intercurrent infections with those organisms that also target villous epithelial cells such as coronavirus, Cryptosporidium, Escherichia coli, coccidia, and others.

Pathogenesis: Unlike in rotavirus enteritis, crypt lumens contain cell debris and crypt cells may be focally hyperplastic, indicating attempts at enterocyte replacement and villous repair. The lamina propria and draining lymph nodes often contain increased numbers of inflammatory cells. A hemorrhagic form of the disease with extensive colitis has been reported.

Although generally a mild and self-limiting disease of neonates, feline enteric coronavirus has been associated with fatal enteritis in a series of cats. Lesions consist of degeneration and loss of enterocytes from jejunal villous tips. Cats 2 months to 7 years old are affected.

Septicemic colibacillosis: Septicemic or enteroinvasive colibacillosis (EIEC) is a disease of newborn calves, lambs, and occasionally foals that have not received sufficient colostrum to develop immunity. Although the lesions produced are generally those of septicemia, similar to those caused by other organisms, infection can localize in the intestine, causing enteritis. Diagnosis is generally made by finding fibrin in any location in the body such as the eye, joints, abdomen, heart sac, meninges, and/or thorax. The bacteria gain entry to the body through the respiratory system, oral cavity, or umbilicus. Fibrinous arthritis, ophthalmitis, serositis, meningitis (polyserositis), and white-spotted kidneys (cortical abscesses) characterize the septicemia (see Fig. 11-70). Mixed bacterial infections often occur with ETEC.

Edema disease: Edema disease, also known as enterotoxemic colibacillosis, is an Escherichia coli (F18ab) infection that is specific for pigs. Edema disease is caused by a bacterial enterotoxin (verotoxin) produced in the small intestine and spread hematogenously via induction of IL-8. This interleukin attracts neutrophils that carry the toxin throughout the body. It is generally a disease of pigs 6 to 14 weeks of age and is usually associated with dietary changes at weaning. It is often noted that the best pigs in a group are the ones affected. Edema disease is characterized by neurologic signs including incoordination, poor balance, weakness, tremors, and convulsions.

Hemolytic Escherichia coli proliferates in the small intestine subsequent to dietary changes and produces a heat-labile exotoxin called the edema disease principle. This systemic toxin (angiotoxin) causes generalized vascular endothelial injury of arterioles and arteries (see Fig. 10-42), resulting in fluid loss and edema. The edema can be found anywhere but is most characteristic in the gastric submucosa (see Fig. 10-80), eyelids (Fig. 7-126), forehead, gallbladder, and mesentery of the spiral colon (Fig. 7-127). In the brain, arterial damage causes focal malacia in the medulla, thalamus, and basal ganglia. These nervous tissue lesions are collectively known as focal symmetric encephalomalacia or swine cerebral angiopathy and are responsible for the variety of clinical signs. Death is due to an endotoxic shocklike syndrome. Some animals suffer from a Shwartzman-like bilateral renal cortical necrosis. Morbidity within a herd is approximately 35%, and all affected animals die.

Postweaning colibacillosis: Postweaning colibacillosis is another specific disease of pigs caused by a hemolytic Escherichia coli. The disease appears identical to enterotoxic colibacillosis of the neonate in that it produces a secretory diarrhea and therefore no lesions in the intestine, although gastric infarcts are common. It is a distinct strain of Escherichia coli, however, and is associated with feed and management changes at weaning.

Enterohemorrhagic colibacillosis: Enterohemorrhagic colibacillosis (EHEC) is described in humans, laboratory animals, and occasionally cattle and pigs. It has not been reported as a field problem in livestock. The pathogenesis of the disease is similar to that of other invasive bacteria such as Salmonella spp. In humans, the colon is affected. A Shiga toxin gene, a locus for enterocyte effacement, and a plasmid encoding for hemolysin are produced by Escherichia coli, which result in hemorrhagic colitis and sometimes the hemolytic-uremic syndrome. These strains are also called VTEC, which are strains based on the Vero (African green monkey kidney) cell line on which the bacteria are sometimes grown. Outbreaks of enteroinvasive colibacillosis in humans are often food-borne illnesses. These organisms are pathogenic because of their acid resistance and ability to survive transport through the stomach. Shiga toxin–producing enterohemorrhagic Escherichia coli O157:H7 rarely causes naturally occurring disease in domestic livestock but often contaminates ground beef. Surveys have indicated that the seroprevalence of Escherichia coli O157:H7 in dairy herds is 38.5%, with an individual cow prevalence of 6.5%, and is most often isolated from the skin surface. This finding is an important reason not to eat undercooked ground beef. Steaks are a different matter because bacterial contamination is only a surface phenomenon, and bacteria are killed by surface searing of meat.

Experimentally, calves may develop necrohemorrhagic or mucohemorrhagic diarrhea. Human disease can be serious, resulting in hemorrhagic colitis, thrombocytopenic purpura, and the hemolytic uremic syndrome. Deer, sheep, cattle, horses, dogs, and rabbits, including laboratory rabbits, may be carriers. Stable flies and fecal contamination of a variety of substances may create fomites.

Attaching and effacing Escherichia coli: Attaching and effacing Escherichia coli (AAEC), also called enteropathogenic E. coli (EPEC), has been infrequently reported in rabbits, calves, pigs, lambs, dogs, and humans. The actual incidence of this disease in domestic animals is unknown. Lesions are characterized by Escherichia coli attachment to the microvillous border of enterocytes and gallbladder epithelium via cups and pedestals (Web Fig. 7-19). Intimin, a bacterial outer membrane protein, facilitates bacterial attachment to the host cell’s membrane, resulting in attachment and effacement. These bacteria also alter a variety of tight junction proteins and therefore cause leakage of enterocyte tight junctions. Gross lesions are not present except that the intestine is dilated and fluid-filled. Colonization of the epithelium by attaching and effacing Escherichia coli is relatively common; disease occurs most often in association with other enteropathogens of calves of this age, namely rotavirus, Cryptosporidium parvum, ETEC, coronavirus, BVD, and coccidia. In contrast to ETEC infection, in AAEC infection the brush border of the enterocytes is disrupted and can be seen on select enterocytes in hematoxylin and eosin (H&E) stained tissue sections. Microvillous disruption results in loss of the glycocalyx digestive enzymes, resulting in maldigestion, malabsorption, and diarrhea. AAEC also stimulates enterocyte apoptosis, Cl⁻ and mucus secretion, and toxin production. AAEC flagellin TLR-5 stimulates IL-8 release by enterocytes, which initiates an inflammatory response resulting in cell death and fluid secretion.

Extraintestinal pathogenic Escherichia coli: Extraintestinal pathogenic Escherichia coli (ExPEC) are gut inhabitants with virulence genes that differ from strains of E. coli that are enteropathogens or commensal organisms of the intestine. They contain fimbrial adhesins for attachment, cytotoxins and hemolysins responsible for tissue necrosis and hemorrhage, and siderophore receptors to sequester iron. ExPEC can be isolated from the feces of many healthy animals, particularly dogs and cats. When the animals are stressed, such as in group housing in shelters, aerosolized bacteria may be inhaled resulting in fulminating necrohemorrhagic pleuropneumonia. Septicemia can result in urogenital infections. In addition, meningitis has been reported in humans. There is concern about the zoonotic potential of these organisms.

Peracute Salmonella septicemia: Peracute Salmonella septicemia is a disease of calves, foals, and pigs. Young animals are generally at greater risk than older animals, although the reasons for this difference are not understood. In foals, the feces of affected animals are typically green. The serovar of Salmonella most often involved in septicemic salmonellosis is Salmonella Choleraesuis. Gross lesions of animals dying of peracute Salmonella septicemia are minimal and are caused by fibrinoid necrosis of blood vessels (Fig. 7-128). Necrosis of blood vessels causes widespread petechiation and a blue discoloration (cyanosis) of the extremities and ventrum of white pigs. Fibrinous polyserositis may be present. Peracute Salmonella septicemia is usually fatal in animals 1 to 6 months of age. Death is usually attributable to disseminated intravascular coagulopathy secondary to the generalized Shwartzman reaction.

Acute enteric salmonellosis: Acute enteric salmonellosis is caused most frequently by Salmonella Typhimurium and occurs in cattle, pigs, and horses. Carnivores are rarely affected. Characteristic of the disease is diffuse catarrhal enteritis with diffuse fibrinonecrotic ileotyphlocolitis. Intestinal contents are malodorous and contain mucus, fibrin, and occasionally blood. The feces have a septic tank odor. Salmonella are enteroinvasive through specific surface bacterial fimbrial (pilus adhesin) antigens. Receptor-mediated endocytosis then occurs. Membrane bound vacuoles then translocate the bacteria to macrophages in the lamina propria. The intact Salmonella induce secretory diarrhea through interference with Cl⁻ channels. They also induce enterocyte apoptosis and recruit neutrophils. Endotoxins induce thrombosis. All these adherence and inflammatory changes are regulated by pathogenicity islands. Multiple foci of hepatocellular necrosis and hyperplasia of Kupffer cells (paratyphoid nodules), when present, are characteristic of acute enteric salmonellosis (see Fig. 8-49, B). Mesenteric lymphadenopathy is usually present. Fibrinous cholecystitis at necropsy is pathognomonic for acute enteric salmonellosis in calves (see Fig. 8-78).

Chronic enteric salmonellosis: Chronic enteric salmonellosis occurs in pigs, cattle, and horses. Lesions are seen principally in pigs that have discrete foci of necrosis and ulceration, principally in the cecum and colon. These are termed button ulcers (Figs. 7-129 and 7-130). Because salmonellosis causes vascular thrombosis and pigs have poor or no collateral blood supply to the rectum (cranial hemorrhoidal artery), in affected animals, rectal strictures develop, with resultant abdominal distention secondary to fecal retention.

Enterotoxemia: Enterotoxemia is produced by one of the five Clostridium perfringens types described previously. Type D occurs most often. Clostridial enterotoxemia most often affects the better-fleshed animals within a group. Outbreaks often follow an abrupt change in the amount or quality of feed such as occurs in an animal being “finished” for sale or slaughter. In foals, enterotoxemia has been associated with feeding materials rich in carbohydrates and proteins. This diet leads to a change in the intestinal microbial balance. Clostridium perfringens proliferates and produces abundant toxin. Clinical signs may be absent before death or may include diarrhea, sometimes with blood. Glycosuria occurs only in lambs with enterotoxemia and is a helpful feature in preliminary necropsy diagnosis. Enzyme-linked immunosorbent assay (ELISA) kits are available for toxin typing (CPA, CPB, ETX) and for the bacteria.

The small intestine, the target organ of clostridial enterotoxemia, typically has serosal and mucosal petechiae, ecchymoses, and paintbrush or diffuse hemorrhage similar in appearance to those of intestinal strangulation. The intestines are atonic and dilated. Emphysematous enteritis is variably present, as is coagulative necrosis of skeletal muscle. Congestive splenomegaly is present. On exposure to enterotoxin, villous tip enterocytes and mid-villous enterocytes degenerate and are sloughed into the intestinal lumen, leaving denuded basement membranes. The exposed basement membranes allow fluid leakage and attract leukocytes into the lamina propria. Death is usually rapid.

Clostridium perfringens type A: Clostridium perfringens type A is the most frequently occurring clostridium in mammals and birds. It is also the most common clostridium found in the environment. Clostridium perfringens type A produces enteric disease in a great variety of animals. These diarrheal diseases are generally mild with minimal damage to the intestinal mucosa. In addition to enteritis, infection produces gas gangrene and other anaerobic wound infections. In the western United States, it causes hemorrhagic abomasitis in young ruminants, often accompanied by severe diarrhea. In the Pacific Northwest, principally in Washington and Oregon, a condition called yellow lamb disease is associated with Clostridium perfringens type A. Death is rapid and accompanied by clinical and pathologic signs of hemolysis, hence the yellow discoloration of the carcass.

Clostridium perfringens type B: Clostridium perfringens type B is the cause of lamb dysentery. This is generally a disease of very young lambs, although older animals may be affected in prolonged disease outbreaks. Unexpected death is usual, but occasionally there is antecedent anorexia and abdominal pain with or without severe bloody diarrhea. Other young ruminants and foals may also be affected. This disease occurs sporadically in the US but is more common in Europe, South Africa, and the Middle East.

Clostridium perfringens type C: Enterotoxic hemorrhagic enteritis affects calves, lambs, and foals during the first few days of life and piglets during the first 8 hours of life. Adult horses may also be affected. Clinical signs vary from none to bloody diarrhea. When piglets are affected, the whole litter dies. Lesions at necropsy include hemorrhagic or necrotizing enteritis of the small intestines, sometimes with gas in the lumen and within the walls of the intestine (Figs. 7-131 and 7-132). Struck, which is also caused by Clostridium perfringens type C, affects adult sheep, goats, and feedlot cattle in winter and early spring and is characterized by hemorrhagic enteritis with ulceration, ascites, and peritonitis.

Clostridium perfringens type D: Clostridium perfringens type D affects fattening sheep, goats, and calves. The disease is diet-related and associated with grain overload or “overeating disease.” The sudden change in diet promotes growth of organisms in the small intestine. The disease is often characterized by unexpected death, sometimes preceded by CNS signs or “blind staggers.” Endothelial cell damage is produced by a bacterial toxin (angiotoxin). This lesion can result in bilateral symmetric encephalomalacia, which is similar in its regional distribution to edema disease of pigs (swine cerebral angiopathy) (see Fig. 14-96). Lesions of Clostridium perfringens type D infection are multisystem hemorrhages, particularly of serosal surfaces. Fibrinonecrotic enterocolitis can also occur in association with the β-2 toxin, at least in goats. Pericardial effusion is present along with mild gastroenteritis. The angiotoxin produces “pulpy kidney disease” of sheep (see Fig. 11-49).

Clostridium perfringens type E: Case reports of necrohemorrhagic diarrhea associated with Clostridium perfringens type E infection are poorly documented. It is safest to state that Clostridium perfringens type E may rarely cause enterotoxemia of lambs, calves, and rabbits.

Peracute hemorrhagic gastroenteritis of dogs: The cause of peracute hemorrhagic gastroenteritis of dogs, also known as canine hemorrhagic gastroenteritis, is undiscovered but is considered likely a result of infection with Clostridium perfringens of unknown type. The disease most often occurs in dogs of toy and miniature breeds younger than 2 years. Blood is observed at the anus before death. As the name of the disease denotes, there is hemorrhagic necrosis of the GI mucosa anywhere from the stomach caudally. Numerous clostridial organisms are present in the intestinal debris but are not attached to intact mucosa. Unlike parvoviral enteritis in which crypts are preferentially destroyed, the crypts are spared in peracute hemorrhagic gastroenteritis.

Lincomycin or antibiotic enteritis: Lincomycin or antibiotic enteritis is associated with antibiotic administration and is seen most commonly in rabbits and horses; both are cecal fermenters. It has been suggested but not proved that antibiotic administration causes death of normal enteric flora, which allows overgrowth of Clostridium perfringens type A. Clinical signs and gross and microscopic lesions are similar to those observed in animals with Clostridium spp. enteritis, but bacterial organisms are often lacking.

Clostridium piliforme: Clostridium piliforme infects multiple mammalian species and is commonly called Tyzzer’s disease. The target organs of Clostridium piliforme vary among affected animals. Although pathogen entry is usually via the intestine, the principal target is the liver, but lesions also occur in the intestine and heart. Intestinal involvement is variable and most common in rodents and rabbits. The enteric manifestations of Tyzzer’s disease are generally in the distal small intestine, particularly the ileum. Colitis occurs in some cats. Mucosal necrosis and edema extend into the muscularis. Definitive diagnosis is made by finding the causative bacillus (best done with silver stains such as Dieterle’s or Steiner’s) in the characteristic hepatic (see Fig. 8-48) or intestinal lesions (Fig. 7-133).

Clostridium difficile: Clostridium difficile spores are common in the environment and in the intestinal tract of many mammals. They cause pseudomembranous colitis in primates, including humans, hemorrhagic necrotizing enterocolitis in foals, necrotizing typhlocolitis in horses (colitis X) and possibly cats, and enteritis in a variety of laboratory animals. Clostridium difficile also affects suckling pigs in outbreaks characterized by mesocolonic edema and typhlocolitis. Dogs, especially those hospitalized, may also shed the organism. The disease-producing ability of Clostridium difficile in the dog is not understood, but its zoonotic potential may be important. The induction of disease by Clostridium difficile is likely dose-related, but the reasons for bacterial overgrowth, apart from those caused by oral antibiotic administration, are not known. The lesions are similar to those produced by Clostridium perfringens infection.

Clostridium spiroforme: Clostridium spiroforme causes enterotoxemia in lagomorphs and rodents. The bacterium is semicircular in vivo and has a coiled appearance in vitro when bacteria are joined end to end. In the rabbit, weaning and/or antibiotic treatment with a concomitant change in cecal flora precede diarrhea and death. Lesions include a dilated cecum with liquid contents. As is the case with other clostridia, the cause is confirmed by mouse lethality studies or Vero cell cytotoxicity studies; the appropriate toxin may be isolated from intestinal contents soon after death of the animal.

Clostridium colinum: Clostridium colinum, also known as quail disease or quail enteritis, is an ulcerative colitis restricted to gallinaceous birds. The disease occurs in birds secondary to stress that is often a result of intercurrent infections. Classically, there is hemorrhagic enteritis of the small intestine often accompanied by necroulcerative enterotyphlitis. Necrohemorrhagic hepatosplenitis is often present. Death is rapid and losses are high, especially in quail (Fig. 7-134).

Chlorellosis and protothecosis: Unicellular and sometimes achlorophyllic algae have been reported to opportunistically cause cutaneous or widely disseminated granulomatous disease in a variety of species including humans, dogs, cats, dromedaries, gazelle, a beaver, cattle, and sheep. These algae are found in a variety of environmental locales, including both fresh and marine water. Primary infection is believed to be in the alimentary tract with chronic bloody diarrhea or through cutaneous wounds. Lesions are often tinted green if the algae contain chlorophyll. In the intestine, the transmural lesions are those of granulomatous enteritis and lymphadenitis. Intracellular algae measuring 5 to 11 µm, including those in giant cells, are visualized by Gomori methenamine silver (GMS) or PAS staining of the thick capsule. Chlorella, unlike Prototheca, which is considered to be its achlorophyllous mutant, contains starch bodies and chloroplasts that are birefringent in H&E sections, PAS positive, and diastase negative. Internal septation of the organisms is present with 2 to 20 sporangiospores.

Rhodococcus equi Enteritis: Rhodococcus equi is a soil saprophyte and a normal inhabitant of the equine intestine. The disease caused by this large, potentially zoonotic, Gram-positive, and facultatively anaerobic rod is often characterized by pulmonary pyogranulomas in foals under 6 months (see Fig. 9-67) and in immunocompromised adult horses and humans, or those with intercurrent disease (AIDS patients). The bacterium is not resistant to neutrophil-mediated destruction but can resist the intracellular environment of macrophages. All pathogenic Rhodococcus equi isolated from horses but not humans have a large plasmid and the encoded surface-expressed lipoprotein VapA, which is associated with virulence. The frequent intercurrence of helminths and Rhodococcus equi infection suggests that migrating larvae aid in distributing the bacterium through the body of the foal. Stringent control of helminth infections may therefore help to reduce or eliminate Rhodococcus equi infections.

Equine abortion, pneumonia, and placentitis have been associated with infection, as have sporadic infections, sometimes fatal, of a wide variety of mammalian species. Rhodococcus equi can be isolated from a large number of otherwise healthy mammals of different species.

When coughed up and swallowed in large numbers, the bacteria enter the intestinal M cells overlying the GALT, resulting in pyogranulomatous lymphadenitis of GALT and lymph nodes and pyogranulomatous ulcerative enterotyphlocolitis.

Intestinal infection commences in Peyer’s patches, which are ultimately replaced by granulomatous inflammation, abscess formation, and necrotic tissue, and the patches are ulcerated. Infection then spreads to mesenteric lymph nodes with a similar result. Macrophages, often laden with intact bacteria, fill the intestinal lamina propria and submucosa, resulting in a markedly thickened, corrugated intestine. The grossly observable abscesses and foci of necrosis and ulceration often correspond to the distribution of GALT (Fig. 7-136). Mesenteric, cecal, and colonic lymph nodes are enlarged, firm, and gray (Fig. 7-137). They, along with the spleen, may contain granulomas and abscesses (see Fig. 13-65). The large number of macrophages and multinucleated giant cells within the lamina propria and lymphoid tissue is characteristic of this infection. Bacteria may be seen within these cells with Giemsa and tissue Gram stains. The florid inflammatory infiltrate expands the intestinal villi and may distort the crypts of the entire intestinal tract.

Contamination of skin wounds by Rhodococcus equi may result in cutaneous ulcerative lymphangitis in horses. Swine cervical lymphadenopathy may also be a result of infection.

Equine monocytic ehrlichiosis: Equine monocytic ehrlichiosis, also known as Potomac horse fever, was first reported in 1983. It appears that the disease was present for at least the previous 5 years. First described in the Potomac River valley of Maryland, Virginia, and Pennsylvania, it is now found throughout the US and elsewhere. The common denominator is a proximity of horses to slow-moving bodies of water.

The causative agent, Neorickettsia risticii—an intracytoplasmic rickettsial pathogen of epithelial cells, macrophages, and monocytes—is found in trematodes in freshwater snails. A reduction in pollution levels of the Potomac River basin is believed to have resulted in an increase in the number of freshwater snails. Mayflies and caddis flies have been implicated in transmission. Horses are believed to become infected by eating the dead flies that may accumulate in water buckets and feed troughs, particularly those under artificial light. Rickettsia are often transmitted by arthropods, and this disease is seasonal in northern latitudes (May through September). Without treatment, one-third of cases with diarrhea die as a result of dehydration.

Experimental evidence indicates that Neorickettsia risticii may be abortigenic. The gross lesions of Potomac horse fever are subtle, consisting of congestion, petechiae, and edema, primarily in the cecum and colon. There is a variable superficial necrotizing enterocolitis. Sometimes the small intestine is affected. Intestinal contents are tan, watery, and malodorous.

Because the experimental reproduction of clinical disease in germ-free animals has not been done, the microscopic appearance of lesions is not certain. Intercurrent bacteria may be responsible for some of the reported lesions. Interestingly, horses with Potomac horse fever have a mild necrotizing typhlocolitis similar in distribution to colitis X and enteric salmonellosis. The nature of the gross lesions is somewhat controversial because experimental infections produce variable results. Like hog cholera, Potomac horse fever is sometimes associated with concurrent Salmonella infection, perhaps accounting for the Salmonella-like lesions. Monocytes and macrophages in all layers of the intestine can be demonstrated with stains, such as Giemsa, to contain Neorickettsia organisms.

Clinical signs associated with Potomac horse fever include fever, watery diarrhea, depression, dehydration, variable colic, laminitis, and subcutaneous edema of the thorax, abdomen, and hind legs. Equine monocytic ehrlichiosis is apparently the same disease known as churrido equino (equine scours), which has been present for more than a century in Uruguay and Brazil.

Equine granulomatous enteritis: Equine granulomatous enteritis is characterized by wasting and hypoalbuminemia and has been reported most often in thoroughbred and standardbred horses younger than 5 years. The pathogenesis of the disease is unknown. In a few cases, Mycobacterium avium was isolated from lesions. The disease is characterized by diffuse or segmental transmural noncaseating granulomatous inflammation of the small and occasionally large intestines. Giant cells are present in about half the cases. The result is a notably thickened bowel (Figs. 7-138 and 7-139).

Clostridial enteritis (colitis X): The severe diarrhea seen in cases of colitis X contains no blood and is rapidly fatal. The cause is unknown. However, the disease is associated with certain environmental and clinical variables. These include exhaustion; shock or other stressors; enterotoxemia, perhaps associated with overgrowth of Clostridium perfringens type A (antibiotic enteritis); Clostridium cadaveris; Clostridium difficile; anaphylaxis; or high protein-low cellulose diets. Lesions are limited to the mucosa of the cecum and colon and consist of edema, congestion, and hemorrhage (Fig. 7-140). The location and nature of these lesions overlap with those of acute enteric salmonellosis and equine monocytic ehrlichiosis. Therefore elimination of Salmonella spp. and Neorickettsia risticii as causes is necessary before a diagnosis of colitis X can be made. Thus colitis X is a diagnosis made by exclusion of other causes. At necropsy, in addition to the intestinal lesions, evidence of endotoxic shock, such as disseminated intravascular coagulopathy, thrombosis, and hemorrhage of the adrenal cortices (Waterhouse-Friderichsen syndrome) can be present, as in salmonellosis and other septicemic diseases.

Hemorrhagic fibrinonecrotic duodenitis-proximal jejunitis: In hemorrhagic fibrinonecrotic duodenitis-proximal jejunitis, also known as anterior enteritis and gastroduodenojejunitis, the morphologic description of the lesions is the same as the name of this idiopathic disease. The disease is characterized microscopically by submucosal edema and a neutrophilic infiltrate of the submucosa and lamina propria. Salmonella and clostridial infections are suspected as the cause. This disease occurs in horses older than 9 years, and the definitive diagnosis is made at necropsy by the characteristic hemorrhagic necrotizing lesions in the small intestine. The duodenum is always involved; jejunal involvement is variable.

Chronic eosinophilic gastroenteritis and multisystemic eosinophilic epitheliotropic disease: Soft stools accompanied by weight loss characterize chronic eosinophilic gastroenteritis and multisystemic eosinophilic epitheliotropic disease, which are uncommon conditions. The inflammatory reaction consists of eosinophils among other inflammatory cells in both nodular and diffuse accumulations within all portions and layers of the GI system, salivary glands, and mesenteric lymph nodes (Fig. 7-141). A circulating eosinophilia may be present. The histology of the condition, especially the presence of eosinophils, suggests a hypersensitivity reaction that in at least one instance was associated with Pythium spp. infection. With the exception of the rare cases with a specific etiologic agent, affected horses die. The disease is associated with an upregulated T_H2 response and increased IL-5 production.

Clinical signs relating to the GI system may include watery diarrhea and hypoproteinemia secondary to protein-losing enteropathy. In humans and occasionally in horses, the lymphoplasmacytic infiltrates in this condition are precursors to lymphoma.

Idiopathic focal eosinophilic enteritis: Idiopathic focal eosinophilic enteritis is characterized by infiltration of eosinophils along with macrophages and fibroblasts in the mucosa and transmurally to the serosa (see Fig. 7-141). The cause of the condition is unknown and is associated with obstructive colic. Resection of the affected portion of the intestine is curative in most cases.

Anaphylactoid purpura: Leukocytoclastic vasculitis associated with numerous discrete foci of necrosis and hemorrhage throughout the intestine and in the mucosa of the larynx and skeletal muscles is termed anaphylactoid purpura in the horse and Henoch-Schönlein disease in humans (see Fig. 15-33). Anecdotal evidence suggests that an Arthus-like hypersensitivity reaction to a streptococcal respiratory infection is the mechanism of lesion production.

Bovine viral diarrhea: Bovine viral diarrhea (BVD), also known as mucosal disease, affects cattle of all ages but is most common in animals 8 months to 2 years of age. In this respect, clinical cases are typically younger than in animals susceptible to Johne’s disease. Animals, including new world camelids, infected in utero or early in life with noncytopathic BVD pestivirus develop a persistent infection. They shed virus throughout their lives. Later in life, if exposed to cytopathic pestivirus, they may develop disease. Multifocal, sharply demarcated erosions and ulcers in the tongue, gingiva, palate (see Fig. 7-3), esophagus (Fig. 7-142), rumen, abomasum, and coronary bands of the hooves characterize BVD. In the intestine, the characteristic lesion is sharply demarcated foci of necrosis in the epithelium over the GALT (Figs. 7-143 and 7-144). Lesions in the stratified squamous epithelium begin in the stratum spinosum. Necrosis of the epithelium is soon followed by the formation of erosions and ulcerations. Villous and crypt enterocytes become necrotic. There is lympholysis in the GALT. Follicular medullary regions of intestinal lymphoid tissue may be filled with cell debris and dead enterocytes. There is commonly a fibrinonecrotic pseudomembrane over the damaged GALT.

Clinical signs may include anorexia, depression, profuse watery diarrhea with staining of the perineum and tail, agalactia, pyrexia, rumen atony, ptyalism, lacrimation, and a mucopurulent nasal discharge. Calves infected in utero may have cerebellar hypoplasia, cataracts, microphthalmia, or renal dysplasia, and other congenital defects develop. Abortions, stillbirths, and mummified fetuses can also result from in utero infection in new world camelids, cervids, sheep, and goats, as well as cattle. Aborted calves often have enlarged hemal lymph nodes. Morbidity in a herd varies from 2% to 50%. All affected animals die.

A more common outcome from BVD infection occurs in immunocompetent animals that are seronegative at the time of exposure to either the cytopathic or noncytopathic virus. Variable signs develop, but they are mostly mild or subclinical. Most cattle in the US have serologic evidence of exposure to nonvaccine BVD. Exotic ruminants may also become infected. Under certain circumstances pigs may become subclinically infected. This is of interest because the viruses of BVD and hog cholera are antigenically closely related. This may cause confusing serologic results when testing hogs for cholera. New world camelids may also succumb to BVD infection, although infections are often subclinical. The diagnosis of persistent infection is by immunohistochemistry of skin biopsies because calves shed large amounts of virus through the skin. Feedlot cattle that are persistently infected are believed to be more susceptible to mannheimiosis, chronic pneumonia and polyarthritis syndrome, salmonellosis, infectious bovine rhinotracheitis, bovine respiratory syncytial virus, and mycoses. Other diagnostic means are virus isolation, reverse transcription PCR (RT-PCR), and antigen-capture ELISA.

Rinderpest: Lesions similar to those of BVD occur in cattle with rinderpest. The morbillivirus associated with rinderpest infects cattle, sheep, goats, pigs, water buffalo, giraffes, wildebeest, and other wild ruminants. Disease spread is via aerosolization and contact with other body secretions. Initial virus replication is in tonsils and pharyngeal and mandibular lymph nodes resulting in viremia. Acute necrosis is typically severe in all lymph nodes and the epithelial lining of the alimentary, respiratory, and reproductive systems, including erosions and ulcers of the oral cavity and nasal planum. These lesions are particularly severe in regions of GALT, similar to BVD. Pale eosinophilic, cytoplasmic, and perinuclear inclusion bodies surrounded by a halo are sometimes seen in epithelia and lymphoid tissue macrophages. Intranuclear inclusions are visible less often. The signature lesion is characteristic multinucleate enterocytes in epithelial tissues, including the intestinal lesions that do not occur in BVD. Postinfection immunity is likely lifelong. Rinderpest does not occur in the US or Europe but is a significant disease in Africa and Asia and is believed to be on the verge of eradication through effective vaccination. In immunologically naïve populations of animals, morbidity and mortality may be high.

Peste des petits ruminants: Peste des petits ruminants is a distinct morbillivirus disease of sheep and goats that causes ulcerative and pseudomembranous lesions of the oral cavity, similar to rinderpest, along with necrotizing tonsillitis, fibrinohemorrhagic enteritis, and bronchointerstitial pneumonia. Syncytial cells and nuclear and cytoplasmic inclusion bodies of epithelial and lymphoid tissues similar to those found in rinderpest are also present. Peste des petits ruminants is enzootic in the Middle East, the Indian subcontinent, and North Africa.

Border disease: The pestivirus causing border disease in sheep and goats is antigenically related to the noncytopathic biotype of BVD virus. Border disease is usually a congenital infection associated with reproductive failure or birth of abnormal lambs and kids. When subsequently infected with a cytopathic virus, they develop lesions similar to BVD of cattle. Border disease has been reported in the British Isles, Australia, New Zealand, and the US.

Malignant catarrhal fever: Malignant catarrhal fever, which is caused by closely related rhadinoviruses (γ-herpesviruses), occurs in a variety of species of ruminants, including cervids and bison. Persistent infection is common in host species, and disease occurs as a result of cross-species transmission. The African form of the disease, caused by alcelaphine herpesvirus-1 (AHV-1) is common in wildebeests and other ruminants. In the US and worldwide, ovine herpesvirus-2 (OHV-2), caprine herpesvirus-2 (CpHV-2), and white-tailed deer herpesvirus (MCF-WTD) are most often reported in ruminants. The respiratory form of the disease, associated with keratoconjunctivitis, is most commonly seen in cattle in the US.

Lesions include widespread lymphadenomegaly, lymphoplasmacytic necrotizing arteritis and phlebitis of the subcutis, and especially in the rete mirabile surrounding the base of the pituitary gland. Hoof walls may be shed. Coagulation necrosis is found in lymph nodes, and lymphoplasmacytic infiltrates are present in the retina, myocardium, brain, spinal cord, and meninges. The alimentary form of the disease is characterized as multifocal ulcerative stomatitis (see Fig. 7-4), glossitis, esophagitis, abomasitis, and enterotyphlocolitis associated with vasculitis. Hemorrhagic cystitis may also be present.

Winter dysentery: Winter dysentery is a somewhat enigmatic, acute, generally nonfatal disease of adult cattle. Although its cause is unknown, a coronavirus has been implicated as causative and can sometimes be demonstrated immunohistochemically in colonic basal enterocytes of affected animals. As the disease progresses in a herd, virtually all members become ill. As the name implies, it is a seasonal disease and additionally occurs only in northern latitudes. Catarrhal ileitis and jejunitis characterize this highly contagious disease.

Mild lesions are noted in the rare animal that dies of winter dysentery. The intestinal mucosa is intact, but there is variable congestion and petechiae of the abomasum and small intestine. The intestine may be atonic. The colon may have congestion and hemorrhage of the colonic mucosal folds, a nonspecific lesion associated with tenesmus (tiger striping).

Acute onset of profuse diarrhea, decreased milk production in dairy cattle, variable depression, and anorexia are characteristic. Malodorous green to black (melena) diarrhea lasts for up to 4 days and may contain fresh blood and mucus. Immunity in dairy herds is protective for years. Older animals are more severely affected than are younger ones. Calves appear to be refractory to disease development. Diagnosis is generally made by epizootic information, clinical signs, its seasonal occurrence, and lack of significant mortality.

Bovine torovirus diarrhea: The shedding of bovine torovirus (BoTV), or bredavirus, has been associated with diarrhea of neonatal veal calves. BoTV is a single-stranded, enveloped RNA virus, which currently cannot be grown in cell culture. BoTV is associated with the presence of other enteropathogens of neonates, including rotavirus, coronavirus, Cryptosporidium, Salmonella, and Giardia. Although it is not uncommon to have intercurrent infections producing diarrhea in calves, especially in the presence of immunosuppression, malnutrition, and other stressors, BoTV may cause disease independently. Necrosis and sloughing of enterocytes on the middle and lower villi, extending into the crypts, are noted on histologic examination. Diagnosis is confirmed by antigen-capture ELISA or RT-PCR in feces in the absence of evidence of other enteric pathogens. Death, when it occurs, is due to dehydration.

Paratuberculosis: Paratuberculosis, or Johne’s disease, has been described in numerous ruminant species. Ruminants are infected from feces-contaminated soil. In cattle, the disease is characterized by intractable diarrhea, emaciation, and hypoproteinemia in animals older than 19 months. In the average infected herd, 32% to 42% of animals are infected. In small ruminants (sheep and goats), the clinical disease is similar to that observed in cattle except that diarrhea does not occur. The pygmy goat is an exception to the course of disease in small ruminants in that some pygmy goats develop explosive diarrhea and die unexpectedly. In other ruminants, the disease has a protracted course and is considered a wasting disease because of the loss of body mass (Fig. 7-145). Newer methods of bacterial classification suggest that the causative bacterium Mycobacterium paratuberculosis should be reclassified as Mycobacterium avium ssp. paratuberculosis.

The causative organisms are very resistant to environmental stressors, particularly in regions with acid soils. After ingestion, the bacilli are transported through M cells and taken up by macrophages. Lesions in the lamina propria of the intestines, particularly in the ileum, include the accumulation of macrophages. There is little correlation between the severity of the gross lesions and the severity of clinical disease. An age-related immune resistance to infection and disease develops in animals older than 2 months. Fetuses can be infected, but disease is delayed until the animals are much older. Isolation of newborns from fecal contamination is a useful measure to reduce the incidence of infection in a particular herd.

Diagnosis is made by observing clinical signs together with the signalment. The gross lesion in Johne’s disease is a chronic, segmental thickening of the ileum, cecum, and proximal colon (Fig. 7-146). The ileocecal valve region is usually affected. Affected segments have a variably thickened, rough, rugose mucosa, often with multiple foci of ulceration. There is mesenteric lymphadenopathy.

Noncaseating granulomas contain numerous foamy macrophages with large numbers of acid-fast organisms (see Fig. 7-146; also see Figs. 3-25 and 13-78). In contrast, sheep, goats, and deer may have tuberculoid (caseating) granulomas in the intestines, lymphatics, and lymph nodes. These granulomas are sometimes mineralized and contain whorled accumulations of epithelioid macrophages with variable numbers of Langhans’-type giant cells. It is more difficult to find acid-fast mycobacteria in these mature granulomas.

Mycobacterium avium ssp. paratuberculosis can be isolated from feces of affected animals, from diseased intestines and regional lymph nodes, and sometimes from a variety of other tissues and fluids, including the liver, uterus, fetus, milk, urine, and semen. Acid-fast bacteria in rectal mucosal scrapings are found in 60% of the cases. Hepatic microgranulomas occur in about 25% of affected animals. Aortic and endocardial mineralization (arteriosclerosis), when it occurs in association with the clinical signs and lesions of paratuberculosis, is specific for Johne’s disease in cattle (see Figs. 10-32 and 10-39). The pathogenesis of this vascular lesion is not well understood but is associated with the severe cachexia associated with the disease. The epizootiology of Johne’s disease leads many to believe it is one of the most important diseases facing the dairy industry. Speculation has existed for many years that Johne’s disease is zoonotic and somehow causative of Crohn’s disease in humans.

Hemorrhagic bowel syndrome of dairy cattle: Hemorrhagic bowel syndrome, also known as fatal jejunal hemorrhage syndrome and intraluminal-intramural hemorrhage of the small intestine, is characterized by intraluminal hemorrhage resulting in blood clots that lead to intestinal obstruction. It is characterized by dark, clotted blood in the feces; variable and multifocal distention of the small intestine; small intestinal ileus; and necrohemorrhagic jejunitis or enteritis (Fig. 7-147). The cause is unknown, but Clostridium perfringens type A is suspected. The mortality rate is high.

Chlamydiosis: Bovine chlamydia (Chlamydophila pecorum) has been recovered from spontaneous enteritis of young calves. After experimental inoculation, newborn calves develop fever and diarrhea within 24 hours and become moribund within 4 to 5 days. Grossly the ileum is most severely affected, but the jejunum and large intestine also have lesions. In diseased segments, the mucosa is congested and marked with petechiae. The intestinal wall and mesentery are edematous. The lumen contains watery, yellow fluid mixed with a yellow, tenacious, fibrin-rich material attached to the surface. Colonic ridges are hyperemic and have small erosions. Bleeding from petechiae and ecchymoses of the colonic or rectal ridges occurs infrequently. Regional lymph nodes are enlarged. Microscopically, villous epithelial cells, enterochromaffin cells, goblet cells, macrophages, fibroblasts of the lamina propria, and endothelial cells of lacteals are parasitized by the chlamydia. The chlamydia are endocytosed and multiply in epithelial cell apices. They subsequently are liberated into the lamina propria. Villi are enlarged by dilated lacteals and infiltrates of mononuclear cells and neutrophils. Crypts of both small and large intestines are dilated and have sloughed epithelial cells and inflammatory exudate (colitis cystica superficialis). The centers of lymphoid follicles of Peyer’s patches are necrotic. The mucosa and submucosa of the intestines are thickened by a diffuse granulomatous reaction. The abomasum also has lesions, and in some calves, foci of inflammation extend transmurally, thereby causing focal peritonitis. Affected calves have diarrhea, fever, anorexia, and depression.

Transmissible gastroenteritis: Transmissible gastroenteritis (TGE) is an important disease in pigs younger than 10 days. Older animals apparently can compensate for the small intestinal damage through fluid and short-chain fatty acid absorption in the large intestine. The coronavirus that causes this disease cross-reacts with but is distinct from the coronavirus that causes feline infectious peritonitis. The virus is inactivated by sunlight, therefore TGE disease occurs mostly in winter. Target cells for the virus are villous enterocytes, therefore lesions consist of notable atrophy of villi of the small intestine (Fig. 7-148). In piglets, epithelial replacement time is much longer than in more mature animals, accounting for the high mortality. Diagnosis is by positive immunostaining of intestinal sections in piglets acutely ill with the disease.

Similar to rotavirus or non-TGE coronavirus infections, the virus is lytic and sloughed enterocytes carry virus into the feces. The difference in pathogenicity between rotavirus and non-TGE coronavirus infections and TGE is the number of villous enterocytes destroyed by a virus. In TGE, most of the villous enterocytes are destroyed and therefore the clinical disease is more severe.

The diarrhea contains odoriferous undigested milk. The loss of the majority of villous enterocytes results in continued significant intestinal malabsorption. Because of fusion of adjacent villi, the enterocyte mass may never fully be restored. Affected surviving animals remain chronic “poor doers.”

Piglets dead from TGE are dehydrated and their perineum is stained with liquid, yellow, fecal material. The small intestine is dilated and thin walled because of the loss of enterocytes, and contains yellow fluid and gas (Fig. 7-149). Mesenteric lymph vessels are devoid of chyle as a result of malabsorption. The diagnosis is partially based on the presence of villous atrophy. The decrease in villous height: crypt depth ratio is marked and may be appreciated subgrossly (Fig. 7-150). Colibacillosis, coccidiosis, cryptosporidiosis, rotavirus infection, and non-TGE coronavirus infection are among the differential diagnoses.

Piglets suffer from acute diarrhea, weight loss, vomiting, and dehydration. Morbidity and mortality, especially in neonates, approach 100% in susceptible herds. Death occurs within 48 hours to 5 days after the commencement of clinical signs. In feeder pigs, transmissible gastroenteritis virus infection causes transient clinical signs with eventual recovery. Sows are susceptible to the virus, and morbidity among the sows is 100%, but the clinical signs are mild and transient (fever, vomiting, inappetence, and agalactia), and none die. Immunity is solid.

Swine dysentery: Unlike most of the other diseases of the porcine gut, swine dysentery is generally confined to the large intestine. The causative bacterium, Brachyspira hyodysenteriae, previously known as Treponema and Serpulina, is a Gram-negative, flagellated, and anaerobic spirochete that acts synergistically with anaerobic colonic flora, such as Fusobacterium necrophorum or Bacteroides vulgatus, to produce disease. This synergism is believed to be partially responsible for the age restriction (8 to 14 weeks old) of the disease because neonatal animals have not yet developed the appropriate anaerobic gut flora. Brachyspira hyodysenteriae produces a cytotoxic hemolysin, which is a virulence determinant.

The gross lesions of the disease closely approximate those of acute enteric salmonellosis except that bloody feces are more usual in dysentery. Weanling pigs 8 to 14 weeks old are usually affected, and the disease spreads rapidly through a herd. Morbidity approaches 90%, and mortality is around 30%. Lesions of mucohemorrhagic enteritis are present in the spiral colon, colon, cecum, and rectum. The intestine often has a fibrinonecrotic pseudomembrane that correlates with the severe diarrheic feces that contains blood, mucus, and fibrin (Fig. 7-151). The diarrhea and electrolyte loss that occur are caused by colonic absorptive failure.

Brachyspira hyodysenteriae is identified by impression smear (Fig. 7-152), dark-field microscopy, immunolabeling techniques, and PCR. It is assumed that a carrier state exists because the disease is enzootic in affected herds.

Lawsonia enteritis: Lawsonia enteritis manifests in a variety of ways as indicated by the number of names applied to it: proliferative enteropathy, proliferative ileitis, intestinal adenomatosis, distal ileal hypertrophy, terminal ileitis, and proliferative hemorrhagic enteropathy. The genus of the causative agent has undergone several recent changes in nomenclature. For many years, this disease was believed to be caused by Campylobacter spp. (Campylobacter sputorum mucosalis, Campylobacter jejuni, Campylobacter hyointestinalis). Newer methods of bacterial classification caused the name to be changed to Ileobacter and now Lawsonia. Pigs older than 4 weeks of age are susceptible; thus this condition is a postweaning disease. Disease is believed to be caused by an unknown interaction of Lawsonia with normal gut flora. The nature of the lesions is a function of the extent of intestinal mucosal necrosis. The disease begins as a bacteria-induced stimulation of small intestinal crypt epithelial cells, particularly in the ileum (Figs. 7-153 and 7-154), where lesions are generally most severe. With time, the lesions progress to necrosis of the proliferating crypt cells with hemorrhage (Fig. 7-155). Thus the morphologic appearance of the lesions varies from case to case. The mechanism of lesion production is not well understood. Infection results in immunosuppression with a reduction in CD8⁺ T and B lymphocytes. In the proliferative form of the disease, the causative bacteria may be seen in apical cytoplasm of enterocytes. The mechanism of enterocyte proliferation may relate to Lawsonia-induced altered transcription of host “alarm response” genes that affect regulation of the cell cycle and cell differentiation. The enterocyte hyperplasia that results may cause release of cytokines that attract macrophages. With severe disease, bacteria are present in macrophages in the lamina propria. This may cause release of tumor necrosis factor-α (TNF-α) resulting in vascular permeability and hemorrhage.

At clinical and necropsy examination, variable amounts of blood and intestinal casts are present in the feces. Microscopically, the comma-shaped bacteria are made visible with special stains, such as Steiner’s, within the mitotically active cells of the small intestinal crypts (Fig. 7-156). The massive mitoses of crypt cells and resultant cryptal crowding and necrosis prevent maturation to absorbent villous enterocytes. There is resultant villous shortening. Mitosis can be so intense that the histologic features suggest neoplasia and a diagnosis of “intestinal adenomatosis.”

Morbidity within a herd is 10% to 15%; mortality is around 50%. In fatal cases, affected pigs usually die within a day of the appearance of clinical signs. Pigs that recover are generally “poor-doers.” A similar organism with associated intestinal proliferation is found in horses, hamsters, ostriches, cervids, and macaques.

Glasser’s disease: Glasser’s disease is characterized by fibrinous polyserositis (pleuritis, pericarditis, peritonitis, arthritis, and leptomeningitis). Although not generally a diarrheal disease, it causes inflammation of the intestinal serosa (serositis). Lesions range from arthritis to peritonitis to leptomeningitis, depending on the serous surface infected. Glasser’s disease generally occurs in 5- to 12-week-old pigs. Mortality of affected animals within a herd is high, but morbidity is low. Although classic Glasser’s disease is caused either by Haemophilus suis or Haemophilus parasuis, porcine polyserositis can be caused by Mycoplasma hyorhinis, Streptococcus suis type II (zoonotic), septicemic salmonellosis, and septicemic Escherichia coli (Fig. 7-157).

Chlamydia infection: Chlamydia has been found in enterocytes of normal pigs and pigs with diarrhea. In gnotobiotic pigs, Chlamydia trachomatis and Chlamydia suis infection result in villous atrophy and villous-tip necrosis. These lesions are most severe in the distal jejunum and ileum. Colonic infection has also been reported.

Intestinal emphysema: Intestinal emphysema (pneumatosis cystoides intestinalis) of pigs and rabbits translates to gas-dilated lymphatics of the intestinal serosa and mesentery. The cause of this condition is unknown, and it is not associated with clinical disease (Fig. 7-158).

Parvovirus enteritis: Parvovirus enteritis of dogs and cats is a severe, usually fatal disease. Because the target cells are those that are rapidly dividing, in the intestine the crypt cells are principally affected. This tropism is called radiomimetic. Identical crypt lesions in felids are sometimes associated with FeLV infection. Initial virus replication occurs in lymphoid tissue. Although there is much overlap in the disease syndrome in dogs and cats, the dissimilarities warrant independent discussion of each species. To complicate matters further, there is a high mutation rate among canine and feline parvoviruses and genetic recombination between the two viruses has been documented.

In the cat, mink, and raccoon, panleukopenia, cat distemper, feline enteritis, and mink enteritis are synonyms for this important disease. Early lesions in the course of the disease are lymphoid depletion and thymic involution. Later, lesions include flaccid, segmentally reddened intestine with serositis. Lesions are generally limited to the small intestine, but colitis occurs in some cats. Villous atrophy occurs secondary to crypt cell destruction (Fig. 7-159). Basophilic intranuclear inclusion bodies are present in enterocytes and lymphocytes early in infection. In germ-free cats with a low enterocyte turnover, the disease caused by feline parvovirus is much less severe. Intrauterine infection causes congenital cerebellar hypoplasia of kittens. The virus, as described previously, is cytolytic and infects dividing cells and thus alters the differentiation of layers in the cerebellum during organogenesis. The clinical disease is characterized by dehydration, depression, and diarrhea and vomiting. Because the bone marrow is a rapidly dividing tissue, panleukopenia dominates the clinical pathologic findings.

Canine parvovirus enteritis first appeared in Europe and the US in 1978. The disease was initially recognized because of the gross and microscopic lesions that were identical to those of feline parvovirus enteritis. Panleukopenia vaccines were effective in preventing this disease in dogs and were used extensively until canine-specific parvovirus vaccines were developed. Rottweilers and Doberman pinschers, which are genetically related, are at increased risk for parvovirus disease even if properly vaccinated.

Canine parvovirus disease initially was described as occurring in three distinct syndromes. Puppies younger than 2 weeks of age had generalized disease with focal areas of virus-induced necrosis in those tissues with rapidly dividing cells. Thus multiple organs and tissues, such as the liver, kidney, heart, vessel, bone marrow, intestine, and lung, were affected. Puppies 3 to 8 weeks of age would sometimes have myocarditis develop for the same reason. Often, initial infection would go undetected, and these animals would die unexpectedly up to 5 months later because of myocardial scarring and conduction failure (see Fig. 10-82). In puppies 8 weeks or older, the disease is identical to that in the cat. Cerebellar hypoplasia has not been induced in puppies.

At necropsy, the dilated, fluid-filled, flaccid, and hemorrhagic small intestine with serositis similar to that of panleukopenia is quite characteristic (Fig. 7-160, A). The contents of the small intestine are brown to red-brown and fluid with a fibrinous exudate, with or without hemorrhage (Fig. 7-160, B). Mesenteric lymphadenomegaly with variable hemorrhage is present. The bone marrow is depleted. Dogs but not cats may have coagulative lymphadenitis associated with severe lymphoid infection.

The intestinal lesion is necrosis of crypt epithelial cells. Surviving epithelial cells are not targets of the virus, but their morphology changes to squamoid to cover the surface of the denuded crypts and later to temporarily cover the denuded villous basement membrane, as replacement cells are not being produced, even though senile epithelial extrusion continues to occur from the villous tips. Severe lesions consist of partially denuded villi over debris-filled crypts, some of which lack an epithelial lining. Because the villous basement membrane is exposed during the continuing extrusion process, villous fusion occurs, resulting in lack of a scaffold for enterocyte replacement once the crypts recover and in permanent villous distortion and atrophy. Hyperplastic crypt epithelium may therefore be present. Inclusion bodies are not present in lymphoid tissue. In bone marrow, erythropoiesis is normal, but granulopoiesis is reduced. Necrotizing colitis may occur but is much less important than the small intestinal lesions. Dogs with hemorrhagic parvovirus enteritis have bloody diarrhea and die from shock within 24 hours. Secondary bacterial infections with endotoxemia are believed to be associated with this syndrome.

Minute virus of canids: Canine parvovirus type 1 produces myocarditis and respiratory disease in young pups. The virus is widely distributed in the canine population, but disease is only diagnosed sporadically. The virus is spread via the oronasal route. Fetal death and embryo absorption occur between 25 and 35 days of gestation. Microscopically, intestinal lesions consist of enterocyte hyperplasia with eosinophilic or amphophilic intranuclear inclusion bodies in the enterocytes of the villous tips of the duodenum and jejunum. Crypt necrosis characteristic of canine parvovirus type 2 infection is not present.

Feline infectious peritonitis: Feline infectious peritonitis (FIP) is a uniformly fatal disease of cats. A nearly identical coronaviral disease has been described in ferrets. Although it affects cats of all ages, the disease is principally found in the young and old. Twelve percent of feline deaths are associated with FIP. The cause of the disease is a coronavirus related to the coronavirus of transmissible gastroenteritis of pigs. The coronavirus of FIP in cats is believed to be a mutated enteric coronavirus. After entry into the body, the first round of viral replication takes place in the lymphoid system. Macrophages are infected and carry the virus systemically. Endothelial cells are activated secondary to upregulation of major histocompatibility complex II. Observations suggest that activated monocytes are critical for development of vasculitis. Lesions are multifocal and most organs, including the CNS, may be affected (see Figs. 14-105 and 14-106). The lesions in the vasculature of the eye are sometimes useful in making a tentative diagnosis of FIP in the live cat, but other diseases, such as toxoplasmosis and systemic fungi, may cause similar lesions (see Figs. 20-69 and 20-139). The “wet form” of the disease is characterized by fibrinous polyserositis (Fig. 7-161); the “dry form” is without the effusive process. Why one form develops rather than the other is not completely understood but may relate to the major type of immune effector cell. The disease often clusters in households, and virus spreads among cats by saliva on shared bowls and utensils or by mutation of an endogenous coronavirus.

Because of the presence of a nonneutralizing antibody, immune complexes develop and Arthus reactions localize in the vasculature. Complement is fixed, and inflammatory cell chemoattractants are produced. Vasculitis results in protein effusion. Thus lesions are vasocentric. The prodromal course of FIP is shortened, and the development and extent of lesions are accelerated in seropositive cats. FIP is usually characterized by progressive wasting because of protein loss. It is unusual for a virus to result in pyogranulomatous lesions, but in FIP the vasocentric deposition of immune complexes results in pyogranulomas. These lesions are single to multiple, white, and raised. On the surface of the kidney, they often are linear, clearly following the renal surface vasculature (see Fig. 11-75). In its “wet form,” FIP is characterized by variable of amounts of thick, stringy, high-protein effusion in body cavities. When placed between gloved fingers, this transudate may be drawn out in strings as the fingers are separated. The transudate is sterile, eliminating most other causes of fibrinous peritonitis. The granulomas are translucent and less than 2 mm in diameter. The “dry form” of the disease is identical to the wet but contains only pyogranulomas and not the exudates.

Histiocytic ulcerative colitis: Because of its occurrence in boxer dogs and the genetically related French bulldog, histiocytic ulcerative colitis has been called boxer colitis. Granulomatous colitis is another term for this disease, although true granulomas are not present. It generally occurs in dogs younger than 2 years. Dogs can have soft feces, but often no diarrhea or weight loss is observed. In some cases, mucus and blood appear in the stool. The lesions, which are visible by proctoscopy, are raised ulcerative nodules (Fig. 7-162). Microscopically the colon is ulcerated and has marked infiltration by macrophages containing PAS-positive material.

Large macrophages with abundant foamy eosinophilic cytoplasm are present in the colonic lamina propria and submucosa early in the disease process. There may be lesser numbers of smaller, mononuclear inflammatory cells, principally lymphocytes and plasmacytes. The PAS-positive material in macrophages has been visualized by tissue Gram stains, electron microscopy, and immunohistochemistry. They likely contain bacteria and the phagolysosomal remnants of digested cells. Evidence suggests that the bacteria are probably Escherichia coli. The massive numbers of engorged macrophages within the lamina propria results in a space-occupying lesion that affects the overlying enterocytes. Enterocyte necrosis results in colonic erosion and ulceration. There is lymphadenopathy, both regional and generalized, characterized by an influx of foamy macrophages in the lymphatic sinuses.

Citrobacter freundii enteritis: Bacteremia and septicemia associated with Citrobacter freundii have been reported to cause mucohemorrhagic diarrhea in dogs with hemorrhagic lesions in the small intestine and colon. It is believed to be a condition of puppies and immunocompromised dogs. Being bacteremic and/or septicemic, many organs and tissues are affected besides the gut. The condition is more common in humans as a nosocomial infection with a high mortality rate. In humans, the route of infection is through the urinary tract, gallbladder, GI tract, or cutaneous wounds. Citrobacter infections should be considered potentially zoonotic.

Canine histoplasmosis: Canine histoplasmosis occurs most often in the Ohio and Mississippi river valleys. This zoonotic systemic fungus can infect the intestine, but pneumonia is more common. Thus the route of infection is inhalation or ingestion. The reservoir is believed to be soil and bird feces. The yeast invades tissue, causes necrosis, and replicates in macrophages. Granulomatous lesions may be present in pulmonary, intestinal, lymphoid, hepatic, and other tissue. At necropsy or biopsy, the intestine has a thickened and corrugated mucosa with ulceration. There is hepatomegaly and mesenteric lymphadenopathy and lymphadenomegaly. Scattered pulmonary granulomas may be present.

In the affected ileum and colon, the lamina propria is widened by macrophages that contain Histoplasma capsulatum (Fig. 7-163). With time, infection may extend transmurally through the intestine and to the lymphoid system. There is hyperplasia of regional lymph nodes, and lymphoid sinuses contain numerous macrophages (see Figs. 13-55, 13-83, and 13-84). Multifocal granulomas with intracellular fungi are in the liver, presumably arriving via the portal vein (see Fig. 8-51).

Signs of intestinal histoplasmosis in the dog include intractable chronic diarrhea with anorexia and its attendant weight loss, lethargy, poor pelage, and anemia. Respiratory signs and peripheral lymphadenitis may be present.

Salmon poisoning: Salmon poisoning is an acute and fatal hemorrhagic granulomatous enterocolitis of the dog and fox that results from consuming salmon carrying the fluke Nanophyetus salmincola. When this trematode harbors Neorickettsia helminthoeca, a 0.3-µm coccoid rickettsia, disease may result. Lesions may extend from the pylorus to the anus. The enteric lesions consist of hemorrhage at sites of GALT necrosis, especially near the ileocecal valves. In the small intestine, trematodes may be embedded in the mucosa. Diagnosis is confirmed by visualizing macrophages in many tissues, including the lymph nodes, lamina propria and brain, containing Giemsa- or Gram-stained elementary bodies (Web Fig. 7-20).

Six to eight days after eating parasitized fish, affected canids become febrile and depressed. There is an oculonasal discharge, severe diarrhea, emesis, anorexia, and splenolymphadenopathy characterized by enlarged tonsils, spleen, and lymph nodes. The mesenteric lymph nodes are often more severely affected than peripheral nodes. Unless treated, affected animals die within 10 days.

Canine multifocal eosinophilic gastroenteritis: Canine multifocal eosinophilic gastroenteritis is an uncommon disease of dogs generally younger than 4 years. It is caused by migrating larvae of Toxocara canis. Therefore this disease occurs in association with poor parasite management.

Larvae of Toxocara canis are ingested, invade the mucosa of the stomach and small intestine, and then become trapped and localized in their self-induced inflammation. Dormant larvae migrate into the uterus and fetuses during late pregnancy. Postpartum, larvae are secreted in the milk of the bitch or ingested from environmental feces. Ingested larvae penetrate the gastric and small intestinal mucosa, enter lymph vessels or the portal vein, and travel to the liver and lungs. They then develop into third-stage larvae and are coughed up and swallowed. In the GI tract, they mature to adult ascarids. In the majority of puppies, ascarid larvae complete their life cycle in several weeks. Alternatively, the larvae are enveloped in granulomas that kill the parasite secondary to immune reactivity. These granulomas may occur anywhere along the parasite’s migration tracts, including most abdominal organs, eyes, brain, and the lungs. Eosinophils are a prominent component of the inflammatory reaction and are attracted to the site of parasite entrapment by the waste products of the larvae. There may be subsequent mineralization of larvae, or they may remain viable for up to 4 years. This condition is especially common in aberrant host species and is called visceral larval migrans. It is an environmental danger where children play in sand or dirt contaminated by feces of infected animals. The ova are relatively resistant to environmental extremes.

Lesions are microscopic to macroscopic and may be quite numerous. As in other inflammatory diseases, there may be regional lymphadenopathy with or without nodules that vary from principally granulomatous to eosinophilic or a mix of the two. Larvae, when present, are surrounded by an eosinophilic, amorphous, fringed material that stains PAS-positive (the Splendore-Hoeppli phenomenon).

In general, canine multifocal eosinophilic gastroenteritis is asymptomatic. However, chronic diarrhea, moderate weight loss, intermittent or persistent eosinophilia, and elevated serum γ-globulin concentrations may characterize this disorder. Serum albumin concentration, absorption tests, and small bowel contrast radiographs usually are normal.

Inflammatory bowel disease: In dogs and cats, this disease is microscopically a lymphoplasmacytic enteritis. Diagnosis is made by biopsy. Breeds with a predilection for this disease include the basenji and the German shepherd. The cause is unknown, but the presence of numerous lymphocytes and plasma cells suggests an immunologic problem. Malabsorption and chronic protein-losing enteropathy can result from the marked infiltrate of lymphocytes and plasmacytes in the lamina propria. In dogs, there are increased numbers of both B and T lymphocytes in the lamina propria of the small intestine (Fig. 7-164). In cats but not dogs, dietary antigens cause some cases of inflammatory bowel disease; therefore control of the disease can be achieved by regulation of the diet. Anecdotal evidence suggests that lymphocytic plasmacytic enteritis in the cat can be a prelude to intestinal lymphoma.

Diffuse eosinophilic gastroenteritis: Although diffuse eosinophilic gastroenteritis has a predilection for the German shepherd breed, it occurs in other breeds of dogs and in cats. It is characterized by recurrent episodes of diarrhea associated with tissue and circulating eosinophilia. The increased concentration of eosinophils in the circulation and within lesions suggests a hypersensitivity reaction to some ingested substance or to parasites. The cause has not been identified. There are no gross lesions. Eosinophils, along with lymphocytes and plasma cells, heavily infiltrate all layers of the mucosa of the stomach and intestine (Fig. 7-165).

Wheat-sensitive enteropathy of Irish setters: Wheat-sensitive enteropathy, a hereditable condition similar to gluten-sensitive enteropathy of humans, is the first described dietary-induced enteropathy of dogs. It is characterized initially by increased numbers of intraepithelial lymphocytes and goblet cells and later by partial villous atrophy, particularly of the jejunum. Dietary therapy is palliative.

Feline ulcerative colitis: Feline ulcerative colitis is grossly and histologically analogous to its canine counterpart, histiocytic ulcerative colitis (Fig. 7-166). The cause is unknown.

Canine senile gastrointestinal amyloidosis: Amyloid located in and around vessels of the submucosal and muscular layers of the alimentary tract and within the mesentery has been reported in dogs. The mechanism and chemical nature of the amyloid deposition has not been determined. Dysfunction of the alimentary tract has not been reported to occur with canine senile gastrointestinal amyloidosis.