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Equine October 2009 (Vol 4, No 8)

Acute Colitis: Infectious Causes

by R. Atherton, BVSc, MSc, DACVIM, MRCVS, Harold C. McKenzie III, DVM, MS, DACVIM, Martin O. Furr, PhD, DACVIM, DVM, M. Amezcua, DVM, MSc, PhD, Robert Friendship, DVM, MSc, DABVP, Catherine Dewey, DVM, MSc, PhD, Merlyn Lucas, DVM, MS, DACT, C. F. M. de Lange, BSc, MSc, PhD

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    Unlike many noninfectious etiologies for which diagnostic testing is limited, tests such as whole blood polymerase chain reaction (PCR) testing and tests for fecal samples (e.g., bacterial culture, PCR testing, toxin ELISAs) are available to detect common infectious causes of acute colitis. However, while these tests may help determine a definitive diagnosis, results are often not obtained in a timely manner, and treatment should not be delayed pending results.

    Salmonella spp

    Salmonellosis is the most frequently diagnosed infectious cause of diarrhea in horses.3 Salmonella spp are gram-negative facultatively anaerobic bacteria. Numerous serotypes can infect horses, with those in groups B (including Salmonella ser Typhimurium and Salmonella ser Agona) and C2 (Salmonella newport) appearing to be associated with disease more often than those in other groups.3 Four clinical syndromes of Salmonella infection are commonly described and have been reproduced experimentally in horses:

    • Inapparent infections; latent or active carrier states
    • Acute diarrhea
    • Depression, fever, anorexia, and neutropenia without diarrhea or colic
    • Septicemia with or without diarrhea
    In acute cases of Salmonella enterocolitis, the first step in the pathogenesis involves disruption of the host's defenses, including gastric pH, gastrointestinal (GI) motility, colonization resistance, and mucosal immunity. This permits colonization of the distal small intestine and the colon by Salmonella bacteria attaching to and entering mucosal epithelial cells in the ileum, cecum, and proximal large colon.3 The common portal of entry into intestinal cells is the brush border, but bacteria can also penetrate via tight junctions.3 Bacteria enter the lamina propria, are phagocytosed by mucosa-associated macrophages, and then multiply intracellularly and initiate local inflammation. Leukocytes are recruited and activated, resulting in production of prostaglandins, leukotrienes, reactive oxygen metabolites, and histamine.4 Damaged mucosal epithelial cells and activated macrophages produce proinflammatory cytokines (e.g., interleukin-1, tumor necrosis factor α), which further up-regulate the local inflammatory response. When these cytokines reach the circulation, they initiate a systemic inflammatory response (e.g., fever, tachycardia, tachypnea). While Salmonella organisms that have crossed the mucosal barrier may enter the bloodstream (either directly or via the lymphatic system), in most cases, bacteria do not disseminate beyond intestinal mucosa and mesenteric lymph nodes.3

    Additional pathogenic mechanisms demonstrated by Salmonella bacteria include toxin production and increased colonic secretion. Salmonella-associated cytotoxin inhibits protein synthesis in mucosal cells, causing morphologic damage and altered permeability.4 Virulent salmonellae also produce enterotoxin similar to the heat-labile toxin produced by Escherichia coli.4 This enterotoxin increases secretion of chloride and water by colonic mucosal cells via a prostaglandin-mediated increase in intracellular cAMP.5 Due to severe tissue injury and the ensuing inflammatory response, acute enterocolitis caused by Salmonella organisms is characterized by severe fibrinonecrotic typhlocolitis with interstitial edema and variable degrees of intramural vascular thrombosis that may progress to infarction.6 Recovery of normal large intestinal function typically takes at least 5 to 7 days, but mucosal injury may be severe enough that normal function will not return and diarrhea will become chronic.

    Clostridium difficile

    Clostridium difficile is an obligate anaerobic, spore-forming, gram-positive rod that is environmentally ubiquitous in spore form. It was first identified in human neonatal feces in 1935. C. difficile organisms are among the first bacteria acquired after a foal's birth, representing a component of the normal GI flora of foals and adult horses.7,8 C. difficile has been reported to cause acute enterocolitis in humans and horses and is now recognized as the primary cause of nosocomial and antimicrobial-associated diarrhea and colitis in humans.9 While salmonellosis is reportedly the most common infectious cause of acute colitis in horses, the incidence of C. difficile"associated colitis appears to be increasing. The involvement of C. difficile in equine enteric disease was first established in 1987, when the organism was associated with diarrhea in 27 of 43 foals in an enterocolitis outbreak.10 Disruption of GI flora by stress, antimicrobial therapy, or other factors allows overgrowth of C. difficile; subsequent release of toxins leads to acute diarrhea.

    C. difficile is considered the most common enteric pathogen in hospitalized humans.11 C. difficile infection is usually associated with antimicrobial therapy; in humans, the risk of contracting the disease increases as antimicrobial treatment continues.12 Additional risk factors for C. difficile infection in horses include severe underlying disease, presence of a nasogastric tube, dietary change, starvation, transportation, and administration of antiulcer medication.7 Hospitalization and antimicrobial therapy are also risk factors for development of C. difficile colitis in horses; in one study, 18 of 43 (42%) horses that developed acute colitis during antimicrobial treatment cultured positive for C. difficile.8 In horses, a wide variety of antimicrobials have been associated with C. difficile diarrhea; however, orally administered antimicrobials, or antimicrobials recycled via the enterohepatic system, have been shown to be most likely to increase the number of clostridial colony-forming units in equine feces.9

    A horse can be infected by vegetative cells or spores of C. difficile from other infected horses, a contaminated environment, or humans. C. difficile spores are not easily destroyed in the environment; they can survive in inoculated feces for at least 4 years.7 Another possible route of infection is proliferation of C. difficile spores in the GI tracts of subclinical carriers.7 If normal GI flora is disrupted (e.g., by a dietary change, antimicrobial administration, or GI surgery), the risk of establishment and proliferation of C. difficile increases. Following ingestion, C. difficile spores survive the low pH of the stomach and upper small intestine, germinate in the terminal ileum, and multiply in the colonic lumen. In the absence of competition from indigenous microflora, the number of bacteria increases, producing toxins that damage intestinal tissue.11

    Assessment of C. difficile involvement is further complicated because not all strains of C. difficile can cause disease.7 Pathogenic strains produce at least five different toxins, of which toxins A and B have been studied in most detail.13 Adenosine diphosphate-ribosyltransferase (binary toxin) was recognized recently, but its role in disease has not been determined.14 Toxin A, an enterotoxin, is thought to have the most significant role regarding induction of fluid secretion, inflammation, and characteristic alterations in intestinal morphology. Toxin A also weakens the tight junctions between epithelial cells lining the colon, helping toxin B enter epithelial cells.4 Toxin A induces neutrophil influx into intestinal tissue as well as mast cell degranulation and secretion of prostaglandins, histamine, inflammatory cytokines, and 5-hydroxytryptamine by activated leukocytes, leading to vasodilatory and secretory responses in enterocytes.8 Toxin B has profound cytotoxic effects in vitro and is more than 1000 times more cytotoxic than toxin A but has demonstrated minimal damage to intact intestinal mucosa.15 However, a toxin A-negative, toxin B-positive strain of C. difficile has been implicated in human colitis, suggesting that toxin B may also be pathogenic.15

    Clostridium perfringens

    Clostridium perfringens is similar to C. difficile in its appearance, physiologic requirements, and environmental behavior. It is considered a normal inhabitant of the GI tract of horses, with positive identification on fecal culture in 12% to 22% of healthy adult horses and 90% of 3-day-old foals.16 Dietary factors such as antimicrobial treatment and stressful stimuli can induce intestinal dysbacteriosis characterized by an overgrowth of C. perfringens. However, unlike C. difficile, which has been recognized as a cause of colitis in horses with no predisposing factors, there is debate as to whether C. perfringens can be a primary cause of colitis in adult horses.3,13 Experimental administration of C. perfringens enterotoxin to ponies has been documented to cause clinical signs of colitis, suggesting that this bacterium can be pathogenic in adult horses.17 Certainly, if C. perfringens overgrowth occurs, large quantities of enterotoxin could be produced, possibly having pathogenic effects on the colon and leading to clinical signs of colitis.18

    The many genetically distinct strains of C. perfringens have variable virulence and produce one or more exotoxins. The pattern of exotoxin production is used to classify C. perfringens into five biotypes: A, B, C, D, and E. C. perfringens type A is the most common clostridial isolate from healthy horses of all ages but is also the most common isolate from adults and foals with diarrhea; therefore, the organism may cause disease if overgrowth occurs. Type C is the most commonly reported clostridial enteric pathogen in foals in North America.4 The identification of C. perfringens types B, D, or E from clinical cases of colitis is rare.

    All five C. perfringens biotypes produce α-toxin, which hydrolyzes lecithin complexes in the membranes of capillary endothelium and other cells as well as in mitochondria. This results in impaired glucose uptake and energy production as well as in activation of arachidonic acid metabolism and protein kinase C signaling pathways in enterocytes, resulting in cellular damage and potential cell death.4 Oral administration of α-toxin in humans was associated with increased secretion by small intestinal mucosal cells; however, no evidence of cytotoxicity was seen.19 The pathogenic significance of α-toxin in horses remains poorly understood.

    Virulent strains of C. perfringens type A and, to a lesser extent, type C typically produce an enterotoxin. This cytotoxin enters cell membranes and forms pores that alter cellular permeability to water and macromolecules, ultimately leading to cellular necrosis.20 β2-Toxin is also of likely pathogenic significance. It is thought to be a pore-forming toxin similar to enterotoxin. It has been documented to be produced by a type of C. perfringens found in horses with colitis, suggesting a pathogenic role of β2-toxin in the etiology of C. perfringens-associated colitis.21

    Potomac Horse Fever

    Potomac horse fever (equine monocytic ehrlichiosis) is caused by the obligate intracellular rickettsial organism Neorickettsia risticii. This organism's role in Potomac horse fever was established more than 20 years ago when inoculation of a horse with blood from an infected horse led to development of clinical signs.22 However, until reliable PCR tests were developed and recent studies completed, the life cycle remained undefined. Studies have now shown that the causative rickettsial organisms live within trematodes. These trematodes are ingested by freshwater operculate snails and aquatic insects that become intermediate hosts.23,24 Bats and birds may be definitive hosts of the helminth vector and a natural reservoir of N. risticii, but the definitive host of N. risticii remains a subject of debate.25 However, the mechanism of transmission of N. risticii to horses has been clarified by challenge studies. Ingestion of numerous intermediate hosts, namely aquatic insects, including stoneflies, mayflies, and aquatic water snails, leads to development of clinical signs consistent with Potomac horse fever, whereas percutaneous inoculation with N. risticii did not result in clinical disease.26

    In horses, N. risticii targets the GI mucosa. The resulting lesions are most severe in the large intestine. The organisms locate within mucosal epithelium as well as macrophages and mast cells of the lamina propria.27 They survive within macrophages by inhibiting production of reactive oxygen species and blocking phagosome-lysosome fusion, thereby avoiding lysosomal digestion.28 Intracellular cAMP increases within infected host cells, leading to decreased luminal reabsorption of sodium ions, increased chloride ion secretion, and decreased water reabsorption in the colon, resulting in profuse watery diarrhea.29 In addition, when infected cells fill with rickettsial organisms, cell lysis occurs. As the disease progresses, fibrinous necrotizing typhlocolitis with severe mucosal ulceration and inflammation of the lamina propria may occur. Vasculitis and intravascular coagulation with perivascular edema in the large intestine are consistent pathologic features of N. risticii infection.30

    While the infectious organism has been identified in aquatic snails from many areas of the world, Potomac horse fever is clinically recognized only in North America, South America, and Europe. The disease is most common from late summer through early fall, with a peak incidence in July and August in the northern hemisphere.4 Potomac horse fever is characterized by fever, anorexia, depression, diarrhea, and leukopenia.31 When Potomac horse fever is experimentally induced by oral inoculation, the latent period is typically 1 to 3 weeks, with a biphasic pattern of fever preceding development of diarrhea. While initial fever may be as high as 107°F (41.7°C), it is often undetected in horses in the field, and there is no indication of infection until onset of the second episode of fever in conjunction with severe depression and diarrhea.26 Moderate to severe diarrhea is known to occur in 75% of horses with Potomac horse fever and may persist for several days.32 While laminitis is a complicating factor known to develop in 20% to 30% of Potomac horse fever cases, the pathogenesis of this condition remains unclear.4 Other complications of Potomac horse fever may include abortion of infected fetuses, vascular thrombosis, renal failure, and protein-losing enteropathy.


    Infectious causes of acute colitis have a common clinical presentation despite variation in associated underlying pathophysiology. Because of the time delay associated with many diagnostic tests, the risk of disease transmission is considerable. Prompt patient isolation and owner education are essential to limiting the chance of disease outbreak. Awareness of the infectious causes of acute colitis should prompt diagnostic testing. If a definitive diagnosis is reached, appropriate treatment can be employed, and the chance for a favorable outcome increases.

    Read the article on pathophysiology and noninfectious causes.

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    Consultant's Corner: How Do I Diagnose and Manage Right Dorsal Colitis? (Winter 2006)

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    1. Rupnik M. Is Clostridium difficile-associated infection a potentially zoonotic and foodborne disease? Clin Microbiol Infect 2007;13:457-459.

    2. Clark RG, Fenwick SG, Nicol CM, et al. Salmonella Brandenburg: emergence of a new strain affecting stock and humans in the South Island of New Zealand. N Z Vet J 2004;52:26-36.

    3. Larsen J. Acute colitis in adult horses. A review with emphasis on aetiology and pathogenesis. Vet Q 1997;19:72-80.

    4. Jones SL. Inflammatory diseases of the gastrointestinal tract causing diarrhea. In: Reed SM, Bayly WM, Sellon DC, eds. Equine Internal Medicine. 2nd ed. Philadelphia: WB Saunders; 2004:884-913.

    5. O'Loughlin EV, Scott RB, Gall DG. Pathophysiology of infectious diarrhea: changes in intestinal structure and function. J Pediatr Gastroenterol Nutr 1991;12:5-20.

    6. Smith BP. Salmonella infection in horses. Compend Contin Educ Pract Vet 1981;3:S4-S17.

    7. Baverud V. Clostridium difficile diarrhea: infection control in horses. Vet Clin North Am Equine Pract 2004;20:615-630.

    8. Baverud V, Gustafsson A, Franklin A, et al. Clostridium difficile: prevalence in horses and environment, and antimicrobial susceptibility. Equine Vet J 2003;35:465-471.

    9. Weese JS, Staempfli HR, Prescott JF. A prospective study of the roles of Clostridium difficile and enterotoxigenic Clostridium perfringens in equine diarrhoea. Equine Vet J 2001;33:403-409.

    10. Jones RL, Adney WS, Shideler RK. Isolation of Clostridium difficile and detection of cytotoxin in the feces of diarrheic foals in the absence of antimicrobial treatment. J Clin Microbiol 1987;25:1225-1227.

    11. Kelly CP, LaMont JT. Clostridium difficile infection. Annu Rev Med 1998;49:375-390.

    12. Starr J. Clostridium difficile associated diarrhoea: diagnosis and treatment. BMJ 2005;331:498-501.

    13. Arroyo LG, Weese JS, Staempfli HR. Experimental Clostridium difficile enterocolitis in foals. J Vet Intern Med 2004;18:734-738.

    14. Magdesian KG, Dujowich M, Madigan JE, et al. Molecular characterization of Clostridium difficile isolates from horses in an intensive care unit and association of disease severity with strain type. JAVMA 2006;228:751-755.

    15. Alfa MJ, Kabani A, Lyerly D, et al. Characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile responsible for a nosocomial outbreak of Clostridium difficile-associated diarrhea. J Clin Microbiol 2000;38:2706-2714.

    16. Tillotson K, Traub-Dargatz JL, Dickinson CE, et al. Population-based study of fecal shedding of Clostridium perfringens in broodmares and foals. JAVMA 2002;220:342-348.

    17. Ochoa R, Kern SR. The effects of Clostridium perfringens type A enterotoxin in Shetland ponies: clinical, morphologic and clinicopathologic changes. Vet Pathol 1980;17:738-747.

    18. McGorum BC, Dixon PM, Smith DG. Use of metronidazole in equine acute idiopathic toxaemic colitis. Vet Rec 1998;142:635-638.

    19. Samuel SC, Hancock P, Leigh DA. An investigation into Clostridium perfringens enterotoxin-associated diarrhoea. J Hosp Infect 1991;18:219-230.

    20. Jones SL, Spier SJ. Pathophysiology of colonic inflammation and diarrhea. In: Reed S, Bailey SR, eds. Equine Internal Medicine. Philadelphia: WB Saunders; 1998:660-663.

    21. Herholz C, Miserez R, Nicolet J, et al. Prevalence of beta2-toxigenic Clostridium perfringens in horses with intestinal disorders. J Clin Microbiol 1999;37:358-361.

    22. Whitlock RH, Palmer JE, Benson CE, et al. Potomac horse fever; clinical characteristics and diagnostic features. Proc Am Assoc Vet Lab Diag 1984:103-124.

    23. Park BK, Kim MJ, Kim EH, et al. Identification of trematode cercariae carrying Neorickettsia risticii in freshwater stream snails. Ann N Y Acad Sci 2003;990:239-247.

    24. Chae JS, Pusterla N, Johnson E, et al. Infection of aquatic insects with trematode metacercariae carrying Ehrlichia risticii, the cause of Potomac horse fever. J Med Entomol 2000;37:619-625.

    25. Gibson KE, Rikihisa Y, Zhang C, et al. Neorickettsia risticii is vertically transmitted in the trematode Acanthatrium oregonense and horizontally transmitted to bats. Environ Microbiol 2005;7:203-212.

    26. Madigan JE, Pusterla N, Johnson E, et al. Transmission of Ehrlichia risticii, the agent of Potomac horse fever, using naturally infected aquatic insects and helminth vectors: preliminary report. Equine Vet J 2000;32:275-279.

    27. Rikihisa Y, Perry BD, Cordes DO. Ultrastructural study of ehrlichial organisms in the large colons of ponies infected with Potomac horse fever. Infect Immun 1985;49:505-512.

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    29. Rikihisa Y. Growth of Ehrlichia risticii in human colonic epithelial cells. Ann N Y Acad Sci 1990;

    30. Cordes DO, Perry BD, Rikihisa Y, et al. Enterocolitis caused by Ehrlichia sp in the horse (Potomac horse fever). Vet Pathol 1986;23:471-477.

    31. Dutta SK, Penney BE, Myrup AC, et al. Disease features in horses with induced equine monocytic ehrlichiosis (Potomac horse fever). Am J Vet Res 1988;49:1747-1751.

    32. Ziemer EL, Whitlock RH, Palmer JE, et al. Clinical and hematologic variables in ponies with experimentally induced equine ehrlichial colitis (Potomac horse fever). Am J Vet Res 1987;48:63-67.

    References »

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