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Enterotoxemia – A review (Proceedings)
Enterotoxemia is characterized by proliferation of and exotoxin production by Clostridium perfringens in the lumen of the gastrointestinal tract. Although limited tissue invasion by the causative organism does occur, most local and systemic lesions result from the local and systemic effects of potent exotoxins produced by certain genotypes of this bacteria.
Enterotoxemia is characterized by proliferation of and exotoxin production by Clostridium perfringens in the lumen of the gastrointestinal tract. Although limited tissue invasion by the causative organism does occur, most local and systemic lesions result from the local and systemic effects of potent exotoxins produced by certain genotypes of this bacteria. Clostridium perfringens is a large, Gram-positive, anaerobic bacillus that exists ubiquitously in the environment and in the gastrointestinal tract of most mammals.1,2 There are five defined types, or genotypes, of C. perfringens (A-E); typing is based on the lethal toxins that they produce: alpha, beta, iota, epsilon and/or enterotoxin.3 All genotypes produce alpha toxin in variable amounts.4,5 Additionally, the beta2 toxin may be produced by type A, as well as by some isolates of types B, C, and E.6 Strains of C. perfringens that carry the plasmid-borne beta2 toxin gene have been isolated from a variety of animals.6,7 Genotyping is based on detection of gene sequences for alpha, beta, beta2, epsilon, and iota toxins and enterotoxin.6-9 It is critical to note that major lethal toxin production is not consistent across clinical isolates within a particular genotype, and the virulence within the species is suspected to be quite variable. Clostridium perfringens type A inhabits the intestine of normal animals and can overgrow in the gut lumen post mortem.1,10 Thus, its isolation should be considered significant only from a fresh cadaver with compatible history, clinical signs, and lesions.
Diets high in concentrates have been shown to increase the rate of isolation of C. perfringens from the rumen and cecum of healthy ruminants.11 Proliferation of C. perfringens in the ruminant gastrointestinal tract, resulting from concentrate feeding or overeating, is considered the pivotal event in the onset of enterotoxemia.10 Unlike type A, C. perfringens types C and D are not found as frequently in the gastrointestinal tracts of healthy ruminants; proliferation of these genotypes occurs in close temporal relation to disease.10 The diagnostic significance of isolation of each genotype of C. perfringens from ruminants with enteric disease is increased if the corresponding major lethal toxins can be demonstrated in gut contents and/or blood,1,12 although few labs offer these assays.
Type A Enterotoxemia and Abomasitis / Abomasal Tympany
The major lethal toxin produced by C. perfringens type A is alpha toxin, which hydrolyzes phospholipids in cell membranes.1 Enterotoxemia associated with C. perfringens type A has been reported in sheep and goats but appears to be relatively rare. 13-15 Experimental intraduodenal administration of C. perfringens type A to goat kids led to transient diarrhea but no fatalities.14
Abomasitis is a sporadic disorder of neonatal to weanling calves, lambs, and kids. This disease is characterized by diffuse, hemorrhagic to necrotizing inflammation of the abomasum. Focal ulceration and/or perforation may occur. Intramural emphysema and edema of the abomasal wall may be present. Clinical signs include lethargy, abdominal tympany, colic, bruxism, fluid distension of the stomach, diarrhea, and death.16 Although the number of case studies on abomasitis is few, upon review of the available literature, the case fatality rate appears to be high (75-100%). 16-20
Primary bacterial or fungal infection, immunosuppression, pica, trauma from coarse feed or trichobezoars, and vitamin / mineral deficiencies have been proposed as etiologic factors. In 1987, investigators detected C. perfringens types A and E in stomach contents of affected calves16 and the following year reproduced the disease experimentally by intraruminal inoculation of C. perfringens type A in calves.17 Although authors of earlier case reports associated copper deficiency with abomasitis and abomasal ulcers in beef calves,21 Roeder and colleagues demonstrated that abomasitis can occur in the absence of copper deficiency.17 Cases of this disease in beef calves have been associated temporally with management practices that cause delays in regular nursing patterns or changes in environment that interrupt normal nursing patterns (e.g. winter storms).21 In dairy calves, poor milk hygiene, intermittent feeding of large volumes of milk, and altered milk temperature have been empirically incriminated as potential contributory factors. Clostridium perfringens type A and type A+beta2 have been isolated from adult dairy cows and beef cattle affected by jejunal hemorrhage syndrome.22,23
Type C Enterotoxemia
Enterotoxemia caused by C. perfringens type C is a commonly fatal disease that occurs in calves and lambs and is suspected to occur on rare occasions in goats.1,10,24 Intake of large quantities of soluble carbohydrate and/or protein is considered a risk factor for the development of type C enterotoxemia.1,10 Ingestion of large volumes of milk or milk replacer, heavy concentrate feeding, or provision of lush forages are risk factors. Beta toxin is the principal major lethal toxin of type C.1,10,25 Beta toxin is inactivated by exposure to trypsin.1,10,25,26 Thus, the lethal effects of beta toxin may be exacerbated in neonates, due to either low pancreatic trypsin production or the presence of trypsin inhibitors in colostrum. This toxin induces necrosis of intestinal wall. Terminally, multisystemic signs of disease can result from absorption of the major lethal toxins as well as other toxins and/or organisms into the bloodstream.
Affected animals are acutely listless and reluctant to nurse. Ataxia, colic, bloody diarrhea, depression, and recumbency soon follow. Extensor rigidity and opisthotonus may be seen terminally, and death usually occurs within hours. Severe hemorrhagic enteritis is the primary gross lesion, most pronounced and consistently found in the distal jejunum and ileum.1,25 Fibrin clots, casts of necrotic mucosa, and blood may be present within the intestinal lumen. Straw-colored or serosanguinous fluid and fibrin may be found within the peritoneal and pleural cavities and the pericardial sac.
Type D Enterotoxemia (Overeating Disease, Pulpy Kidney Disease)
Clostridium perfringens type D causes enterotoxemia in small ruminants of all ages;1,10disease in cattle appears to be very rare.27 Clostridium perfringens type D is not commonly detected in the gut of normal ruminants.10 Passage of soluble carbohydrates or protein into the small intestine is thought to induce rapid replication and elaboration of epsilon toxin from this organism.24 Unlike beta toxin, however, epsilon toxin is activated by intestinal and pancreatic proteases.1 Once absorbed into the bloodstream, epsilon toxin causes loss of endothelial integrity, increased capillary permeability, and edema formation in multiple tissues.28
Type D enterotoxemia in sheep is typically a peracute illness, and affected sheep are frequently found dead. If a live ovine case is detected, neurologic signs predominate. Recumbency, hyperesthesia, lateral recumbency, convulsive paddling, and opisthotonus are apparent within hours. Glucosuria is frequently present but diarrhea is not.29 At necropsy examination, the peritoneal, pleural, and / or pericardial spaces are filled with variable volumes of straw- or red-colored fluid that may contain fibrin clots. Petechial hemorrhages are often visible on the visceral surfaces. Pulmonary and mesenteric edema may be evident. Gross lesions of the intestinal tract are frequently absent in affected sheep. Dipstick analysis of urine collected from the bladder frequently reveals the presence of glucose. The renal cortex may be softened (hence the term "pulpy kidney"), although this is a nonspecific autolytic change. The thalamus and cerebellum may be appreciably soft, with scattered hemorrhages therein. Occasionally, no gross lesions are seen in ovine cases of type D enterotoxemia.24
Unlike sheep, goats affected by type D enterotoxemia more consistently show signs of gastrointestinal dysfunction, and gross and histological lesions are more consistently found in the gastrointestinal tract.30-34 In the peracute form of this disease, affected goats may be found dead. Abdominal distension, vocalizing, colic, tachypnea, and watery diarrhea containing fibrin, mucus, or strands of blood may occur. Recumbency, respiratory distress, convulsions, and death are seen within hours of the onset of signs. Glucosuria is inconsistently present. The most prominent gross postmortem lesion in goats is fibrinohemorrhagic colitis, usually most severe in the spiral colon.34 Luminal casts of fibrin, blood, and mucus may be present, and a pseudomembrane may form in affected colonic segments. Additional findings include pulmonary edema, fluid and fibrin in the body cavities and heart sac, and ecchymotic hemorrhages.
Prevention of Enterotoxemia
Presentation of excessive amounts of starch, sugar, or soluble protein into the stomach and/or intestine is considered pivotal in the development of enterotoxemia; thus, prevention of this pivotal event is essential. Evaluation of dietary energy, fiber content and forage length, bunk space, animal hierarchy within a pen, feeding frequency, the rate and magnitude of changes in ration between successive production groups, and feed mixing practices is essential to identify and correct problems with carbohydrate overload. Turnout onto lush pasture should be gradual, with the time allowed for grazing increased incrementally over several days. Prevention of enterotoxemia in nursing animals requires consideration of environmental or management factors that may trigger changes in milk composition or volume for lactating dams. Intermittent provision of high – energy supplements to range animals may trigger changes in milk production. Similarly, management practices that cause prolonged interruption of suckling must be made time-efficient to prevent milk engorgement by neonates. To that end, during winter storms, encouraging dams to stand and eat by providing hay may encourage more frequent nursing than if the animals were left to "sit the storm out."
Vaccination is considered to be the cornerstone of preventive programs for clostridial diseases in livestock.27, 35 In the following review of the literature, the reader should understand that the conclusions reached in these studies should be related to the specific vaccine product(s) tested in each trial. For sheep, immunization against the major toxins of C. perfringens types C and D is warranted; tetanus is also considered an essential component of a flock immunization program.35-37 In a 1962 study in sheep, Sterne and colleagues demonstrated that a multivalent, alum adjuvanted, formalin-inactivated clostridial bacterin - toxoid administered to sheep in two doses induced titers deemed protective against the beta and epsilon toxins of C. perfringens.38 In another study, antibody titers to epsilon toxin of C. perfringens type D were induced in sheep immunized with a two-dose series of a multivalent (8-way) clostridial vaccine. 39 Immunization of ewes 3 weeks before lambing has been shown to induce colostral antibody titers against epsilon toxin that were adequate to impart protection of lambs for up to 12 weeks of age. 40 In that study, adding a 2-dose immunization of the lambs at either day 1 and 21 of age or day 21 and 42 of age did not significantly change the titer of passively protected lambs. Repeat immunization of lambs with a C. perfringens C and D and tetanus toxoid or a multivalent 8-way clostridial vaccine is recommended at 6-10 weeks of age and again 4 weeks later.36 Feeder lambs and replacement ewe lambs should receive a booster immunization following weaning.36
Administration of multivalent ovine enterotoxemia vaccines twice annually to goats has been demonstrated to be ineffective protecting goats against fatal type D enterotoxemia.31 Goats respond variably to the epsilon toxin in vaccines labeled for sheep.33 The disparity in protection among the two species may reflect disparate mechanisms of disease. In sheep, the majority of pathologic lesions appear to be the result of translocation of epsilon toxin from the gut to remote organs; adequate titers of circulating antitoxin antibodies prevent disease. In goats, however, the more localized disease process (enterocolitis) does not appear to be effectively or consistently curtailed by humoral anti-epsilon toxin antibodies.32-34 Conventional vaccines with aluminum hydroxide adjuvants induce a lesser titer in goats than vaccines with other adjuvants.41 Existing C. perfringens C and D toxoids may need to be administered to goats more than twice per year to confer partial protection.31
Administration of C. perfringens type C and D to cattle has been shown to induce protective titers against both the beta toxin42 and epsilon toxin43 in recipients. For neonates, immunization of pregnant cows and heifers has been shown to produce antitoxin titers considered adequate for protection in colostrum – fed calves.43 Many ranchers immunize calves with multivalent clostridial vaccines prior to weaning, but in many cases, repeat immunization of calves to provoke an anamnestic titer is not consistently performed during the preweaning period. Troxel and colleagues43 determined that vaccination of colostrum-fed calves (from immunized dams) with a multivalent clostridial vaccine at 50-53 days of age and again at weaning at ~170 days produced titers that were not considered protective for calves during the preweaning period. The authors concluded that this 4-month gap between the first and second immunization may not be optimal for herds in which clostridial diseases occur in preweaned calves. In another study, immunization of colostrum-fed calves (from immunized dams) at 3 weeks of age with a single-dose clostridial bacterin-toxoid did not significantly affect type C or D antitoxin titers over the first 4 months of life; however, significant differences in antitoxin titers among recipients of different vaccines were apparent.44 In a prospective (cattle) feedlot study involving nearly 19,000 animals, death losses were compared among calves immunized against clostridial diseases and those that were not.46 Treated calves were administered a 7-way clostridial vaccine at arrival and 30 days later. Reduction in death loss in the vaccinated calves, weighed against purchase price and vaccine cost, provided an additional net profit of over 10 dollars per vaccinate.46