Diseases of the Hematologic, Immunologic, and Lymphatic Systems (Multisystem Diseases)

Chapter 16 Diseases of the Hematologic, Immunologic, and Lymphatic Systems (Multisystem Diseases)



Christopher Cebra, Margaret Cebra



Basic Hematology


An adequate volume of blood for hematologic and biochemical analysis is best obtained from the jugular vein of sheep and goats. The animal should be restrained in a standing position (for goats or sheep) or tipped up (for sheep only) with the head turned away from the jugular vein to be used. Ideally the animal should be restrained by someone other than the operator who will collect the blood, although with sheep, the same person may be able both to provide the necessary restraint and to collect blood if the animal is tipped up or a halter is used (Chapter 1; see Figure 1-5, A and B). The animal should be at rest and handled as gently as possible to minimize stress. The operator parts or clips the wool or hair to visualize the jugular vein and then uses the hand not holding the needle to apply digital pressure proximally just above the thoracic inlet to block blood movement through the vein. The vessel may take a second or more to distend after pressure is applied. The operator may then use the needle-bearing hand to “strum” the vessel, causing the blood to oscillate. If in doubt about whether the distended vessel is the jugular vein, the operator can release the hand placing pressure on the vessel and observe whether the distended vessel disappears; if it does, the distended vessel probably was the jugular vein. Also advisable is to avoid vessels that pulsate, because these probably are the carotid arteries. The area should be cleaned with alcohol or other disinfectant, water, or a clean, dry gauze sponge. An 18- or 20-gauge, 1- to 1.5-inch needle usually is adequate to collect blood from an adult sheep or goat, whereas a 22-gauge needle may be used in a neonate (see Figure 1-5, A and B). The skin of adults or males may be thicker and more difficult to penetrate with the needle. A syringe or evacuated tube attached to a Vacutainer (Becton Dickinson Inc., Rutherford, New Jersey) can be used to collect blood. The needle should be plunged through the skin into the vein at an approximate 30-degree angle. The blood should not come out of the vessel in pulsatile waves; observation of such pulsatility is suggestive of an arterial stick.


After aseptically obtaining an adequate volume of blood, the operator removes the needle and releases the pressure on the vessel near the thoracic inlet. Pressure should be applied to the site of puncture for a minute or more to prevent extravascular leakage of blood and hematoma formation. The blood should be carefully transferred to a vial containing the appropriate anticoagulant to prevent red blood cell (RBC) rupture. Goat erythrocytes are small and particularly prone to hemolysis. To minimize this problem, goat blood should be collected with a needle and syringe, not a Vacutainer. White blood cell (WBC) differential distribution, individual blood cell staining characteristics, and morphology may be assessed by microscopic examination of a stained blood film. The differential distribution provides more information than total WBC count, because inflammatory conditions in sheep and goats often result in a shift in neutrophil populations toward more degenerate, toxic, or immature forms without changing the overall WBC count.1 The preferred anticoagulant for a complete blood count (CBC) is ethylenediaminetetraacetate (EDTA), and tubes should be filled to capacity to ensure the proper blood-to-anticoagulant ratio. Blood samples should be processed as soon as possible after collection. If a delay is anticipated, the blood sample should be refrigerated (at 4° C), and an air-dried blood smear should be made because prolonged contact of blood with EDTA causes changes in WBC morphology and the separation of some RBC parasites. Blood can be refrigerated for 24 hours and still yield an accurate CBC.


A reference range for hematologic data for sheep and goats is presented in Table 16-1 (see also Appendix Tables 2-1 and 2-2). Goats tend to have a low mean corpuscular volume (MCV) because of their small erythrocytes. Sheep and goats younger than 6 months of age tend to have lower hematocrit, RBC count, hemoglobin, and plasma protein concentrations, as well as a higher total WBC count. Neonates often have a high hematocrit at birth that decreases with colostral ingestion. Lactating animals may have decreased hematocrits, RBC counts, and hemoglobin concentrations. Animals grazing at high altitude (mountain goats and bighorrn sheep) tend to have increased RBC counts, hematocrits, and hemoglobin concentrations.


TABLE 16-1 Normal Hematologic Parameters For Sheep And Goats



































































Parameter (Units) Adult Sheep Adult Goat
Hematocrit (%) 27-45 22-36
Hemoglobin (g/dL) 9-15.8 8-12
Red blood cell count (×106/μL) 9-17.5 8-17
Mean corpuscular volume (fL) 28-40 15-26
Mean corpuscular hemoglobin concentration (g/dL) 31-34 29-35
Platelet count (×105/μL) 2.4-7.0 2.8-6.4
Total white blood cell count (/μL) 4000-12,000 4000-13,000
Segmented neutrophils (/μL) 1500-9000 1400-8000
Band neutrophils (/μL) 0 0
Lymphocytes (/μL) 2000-9000 2000-9000
Monocytes (/μL) 0-600 0-500
Eosinophils (/μL) 0-1000 0-900
Basophils (/μL) 0-300 0-100
Total plasma protein (g/dL) 6.2-7.5 6.0-7.5
Fibrinogen (mg/dL) 100-600 100-500


Additional Hematologic Assessments for Anemia and Other Diseases



Bone Marrow Aspiration and Biopsy


Bone marrow aspirates and core biopsy samples taken from sites of active erythropoiesis can be useful to evaluate erythrocyte production and determine the cause of anemia and other hemogram abnormalities. The sites of biopsy in sheep and goats include the sternebra, femur, and ileum. The procedure should be done with use of chemical sedation or with the animal under general anesthesia (see Chapter 18). The area over the biopsy site is clipped and surgically prepared; the operator should wear sterile gloves to maintain asepsis. Aspirates can be obtained by inserting a sterile needle attached to a 3- or 6-mL syringe containing one or two drops of EDTA through the bone and into the bone marrow. Drawing back on the syringe plunger several times may aid in the procurement of an acceptable sample; such a sample may consist of as little as 0.5 mL of bone marrow. If the sample is going to be processed immediately, no anticoagulant is required. Core samples are obtained using a Jamshidi or Westerman-Jensen biopsy needle. The skin is incised with a scalpel and the biopsy needle is inserted into the bone and turned several times to obtain the specimen. More than one site may be used. The operator then closes the skin with sutures or staples.


Biopsy samples are preserved by placing them in 10% neutral buffered formalin solution. Impression smears can be made from these samples by gently rolling them on a clean glass slide before placing them in the formalin solution. Information obtained from bone marrow samples includes subjective data regarding cell density, megakaryocyte numbers, abnormal cells, maturation patterns of RBCs and WBCs, and the ratio of erythroid to myeloid cells. Prussian blue stain can be used on bone marrow to demonstrate iron stores.


Bone marrow aspiration and biopsy are painful and invasive procedures. Therefore animals should receive prophylactic antibiotics and appropriate antiinflammatory drugs.



Blood Cultures


Blood cultures can be useful in diagnosing bacteremia in an intermittently or persistently febrile sheep or goat or an animal with numerous sites of organ infection. Ideally the sample should be obtained before institution of antimicrobial therapy. If this is impossible, however, antimicrobial therapy should be discontinued 48 to 72 hours before sampling. Samples should be taken before and during febrile episodes. The jugular vein is most commonly used to obtain a blood culture. As described previously, the skin over the jugular vein should be clipped and surgically prepared. The person collecting the blood sample should wear sterile gloves and use a sterile needle and syringe. Blood samples should be placed immediately in a blood culture flask. The chances of obtaining a positive culture from bacteremic animals increases with the size of the sample up to about 30 mL, but adding more than the recommended amount to any one culture vial may overwhelm the capacity of the specialized antibiotic-absorbing resins within the flasks. The clinician should change the needle on the sample syringe after collecting the blood and before putting the sample in the culture medium. Samples should be refrigerated until they can be sent to a diagnostic laboratory, where aerobic and sometimes anaerobic cultures are performed.



The Famacha System of Assessing for Anemia


As an alternative to hematologic testing, comparing conjunctival color against swatches on a standardized FAMACHA chart has been used as a rapid and inexpensive assessment for anemia in whole flocks, primarily to evaluate the impact of Haemonchus contortus and other blood-sucking parasites.2,3 Results from a number of trials have yielded fair to good sensitivity for packed cell volume and Haemonchus load in both sheep and goats. As with body condition scoring systems, it is essential to calibrate assessors to ensure consistency in using this system.4 Also, some breeds “read” differently on the cards, and use of an electronic color analyzer, although more expensive and less field-friendly, may detect anemia earlier5 (see Chapter 6).



Changes in the Hemogram


The most common and significant abnormality on the hemogram is anemia. In sheep and goats, anemia occurs most commonly after blood loss and as a result of toxin- or parasite-induced hemolysis or chronic disease. Blood loss usually is covert and commonly is caused by gastrointestinal or external parasites. Overt blood loss usually is caused by major trauma such as that from dog bites or severe lacerations of other cause or is a complication of castration or dehorning. CBC values appear normal immediately after acute blood loss. However, after a few hours of fluid redistribution, anemia and hypoproteinemia are evident. Evidence of red cell regeneration (macrocytosis, reticulocytosis, nucleated red cells) should appear within a day or two of the blood loss.


Hemolysis occurs most commonly after ingestion of toxic plants, RBC parasitism, intravenous injection of hypotonic or hypertonic agents, contact with bacterial toxins, water intoxication, or immune-mediated destruction of opsonized erythrocytes. Ingested toxins include sulfur compounds from onions and Brassica plants (kale, rapeseed [the source of canola oil]),6–9 nitrates, nitrites, and copper.10–13 Except for that caused by copper, hemolysis usually occurs within a day or two after ingestion. Copper toxicosis can occur after acute overingestion but more commonly is seen in animals that are chronically overfed copper and suffer some stressful event. Goats are more tolerant of excess copper than sheep, and certain breeds of sheep, particularly the Suffolk, are highly sensitive to copper toxicosis (see Chapters 2, 5, and 12).


Hemolytic bacterial toxins include those from Clostridium perfringens type A, Clostridium haemolyticum, and Leptospira interrogans.14,15 Intraerythrocytic parasites include Anaplasma spp., Mycoplasma (Eperythrozoon) ovis, and Babesia spp.16–20 Immune-mediated RBC destruction is very uncommon except with parasitemia or the administration of certain drugs (penicillin) or bovine colostrum to small ruminant neonates.21 Rapid reduction of plasma osmolality can lead to osmotic lysis of erythrocytes. This can occur locally as a sequela to rapid intravenous injection of hypotonic substances or after ingestion of a large quantity of water after a period of water deprivation and dehydration (water intoxication). Selenium and copper deficiency also have been associated with Heinz body anemia.22


Parasite infestation, opsonization, and ingestion of toxic plants typically are the cause of extravascular hemolysis. Subsequent removal of damaged erythrocytes by cells of the reticuloendothelial system results in anemia, pallor, weakness, depression, icterus, and dark urine. Bacterial toxins, changes in plasma osmolality, and copper toxicosis cause intravascular hemolysis, resulting in the additional signs of hemoglobinemia and hemoglobinuria. Other disease manifestations such as fever, neurologic abnormalities, and sudden death may be associated with specific diseases. Signs of regeneration should be seen on the hemogram 1 to 2 days after the onset of hemolysis.


Anemia that is not related to the loss or destruction of erythrocytes usually results from a lack of erythrocyte production. By definition, these anemias are nonregenerative. Although mild forms may exist in pregnant sheep and goats and animals deficient in vital minerals (e.g., iron, selenium, copper, zinc), the most common cause of nonregenerative anemia is chronic disease. Under such conditions, iron is sequestered in an unusable form in the bone marrow; staining a marrow sample with Prussian blue stain will reveal large iron stores, differentiating this disease from iron deficiency anemia. The causes of anemia of chronic disease are numerous and include infectious conditions (e.g., pneumonia, footrot, caseous lymphadenitis), malnutrition, and environmental stressors.1



Treatment of Anemia


In most instances, anemia does not require treatment. Unless loss of RBC mass is rapid and severe, the affected animal usually is able to compensate for the decreased oxygen-carrying capacity by decreasing activity. Of importance in this regard is that anemia often first becomes apparent to the manager of a sheep or goat flock when animals appear overly stressed or die during movement or handling.


If possible, the cause of the anemia should be addressed. Interventions can involve strategies to control internal and external parasites, changes in the diet, and treatment of infectious diseases. Maintaining adequate hydration is essential in animals with intravascular hemolysis to avoid hemoglobin-induced renal tubular damage. Specialty compounds such as molybdenum salts (e.g., ammonium molybdate) plus sulfur or penicillamine for copper toxicosis13 and methylene blue (15 mg/kg in a 4% solution in 5% dextrose or normal saline intravenously) for nitrate toxicity usually are too expensive or difficult for application on a flockwide basis but may be useful in valuable individual animals. Veterinarians should be aware that methylene blue is no longer approved for use in food-producing animals (see Chapter 12).


Animals with severe acute blood loss or hemolysis may benefit from a whole blood transfusion. Because transfusion reactions are rare and strong erythrocyte antigens have not been identified in sheep and goats, almost any donor of the same species is acceptable for a first transfusion. Cross-matching can be done to ensure compatibility, which becomes more important if the animal receives more than one transfusion. Blood should be withdrawn aseptically from the donor and collected by a bleeding trocar into an open flask or by a catheter into a special collection bag. Blood should be mixed at a 7.5:1 ratio with acid-citrate dextrose, or 9:1 with 2% sodium citrate, or another suitable anticoagulant, and administered through a filtered blood administration set. If the jugular vein is not accessible, blood may be infused into the peritoneal cavity, but the slower absorption from that site makes it less effective for treating acute blood loss. The first 15 to 30 minutes of administration should be slow. If no reaction is seen (fever, tenesmus, tachypnea, tachycardia, shaking), the rate may be increased. Transfused erythrocytes may survive only a few days, so it is important to address the original cause of the anemia.1



Changes in the Leukogram


Peripheral WBCs include granulocytes (neutrophils, eosinophils, and basophils) and mononuclear cells (lymphocytes and monocytes). Immature forms of neutrophils and lymphocytes may be seen during severe inflammatory diseases. Abnormalities of the neutrophil line usually constitute the best cellular evidence of inflammation in small ruminants, and inflammation is almost always a sequela of infection. An increase in neutrophil numbers and their proportional contribution to the total WBC count usually is seen in mild gram-positive, subacute, or chronic bacterial infections. Animals with more severe disease may exhibit high or normal counts, but a greater proportion of the neutrophils will display toxic changes or be immature forms (band cells, metamyelocytes, or myelocytes). In severe, acute inflammation and many diseases caused by gram-negative bacteria, a temporary reduction in neutrophil numbers is observed, often with a concurrent shift toward more toxic or immature forms. If the animal survives the peracute disease, neutropenia should resolve over 3 to 4 days, mediated first by an increase in immature cells and later by a mature neutrophilic response. Another important cause of increased total and relative neutrophil counts is stress (or glucocorticoid administration), which inhibits neutrophil margination and extravasation, thereby increasing the number of these cells in the midstream blood.


Increases in eosinophil counts usually are related to exposure to eukaryotic parasites. Decreases are rarely of clinical significance and may be seen as part of the stress response. Idiopathic allergic-type reactions also are indicators of a pathologic process but are very rare. Increases in basophils are rarely clinically significant.


Increases in lymphocyte counts often reflect chronic inflammatory disease such as that seen with internal abscesses. In rare cases, lymphocytosis may feature abnormal, blast-type cells, indicating a lymphoproliferative neoplasm. Lymphopenia is an important part of the stress response; nevertheless, the clinician must keep in mind that many diseases stimulate a stress response. Therefore lymphopenia and neutrophilia may represent either stress or inflammation, and an examination of neutrophil morphology and determination of plasma fibrinogen concentrations may be useful in distinguishing between the two situations. A high fibrinogen concentration, toxic changes, and high counts of immature neutrophils indicate inflammation under those circumstances. Blood monocyte counts also may indicate stress or chronic inflammation. The difficulties in interpreting individual cell count abnormalities highlight the importance of obtaining a differential WBC count and description of cellular morphology in assessing sick sheep and goats.


Leukogram abnormalities rarely lead directly to specific treatment. It is far more common and useful to use the information from the leukogram to develop a plan to treat the disease responsible for the abnormality.



Assessment of the Lymphatic System


Palpation of external lymph nodes is part of a thorough physical examination. Lymph nodes that can be identified by this means in normal sheep and goats include the submandibular, prescapular, and prefemoral nodes. None of these should be prominent or painful on palpation. Additional nodes that may be palpated occasionally in normal animals include the parotid, retropharyngeal, supramammary, perirectal, and popliteal nodes. Internal lymph nodes that may be identified during specialized diagnostic procedures include the mediastinal, mesenteric, and other abdominal nodes.


Enlargement of lymph nodes may be focal, multifocal, or generalized. Identification of a single enlarged superficial node does not always rule out a multifocal or generalized disorder, because the status of the internal nodes often cannot be determined. Enlargement generally indicates either inflammation or neoplasia. Inflammatory enlargement typically is related to an associated disease with an infectious component. Small ruminants are particularly sensitive to lymph node–based infections (e.g., caseous lymphadenitis), so the search often does not extend beyond aspirating or draining the lymph node itself. Neoplastic enlargement almost always results from lymphosarcoma.



Disease of the Lymphatic System



Lymphosarcoma



Pathogenesis


Neoplastic transformation of a member of the lymphocyte cell line leads to unregulated clonal expansion of that cell. The cause of transformation is usually unknown; in rare cases, especially in flock outbreaks in sheep, it can be linked to exposure to the bovine leukemia virus, which has occurred experimentally and as a result of the administration of whole blood Anaplasma vaccines. Whether the bovine leukemia virus can induce lymphosarcoma in goats is still unclear. Proliferation of lymphocytes leads to mass lesions and infiltration of viscera. These changes cause physical obstruction (to breathing, blood flow, urination, defecation), ulceration of mucosal surfaces (blood loss, bacterial invasion), immune system dysfunction, organ failure, and generalized malaise and cachexia. Tissues masses may be internal or visible on external examination.



Clinical Signs


Signs vary according to the site of the masses. Slowly progressive weight loss is the most common finding. In some cases, expansile masses are noted; at first they usually are presumed to be caseous lymphadenitis abscesses. Most masses form at the sites of internal or external lymph nodes. Leukemia is rare. The most common abnormalities are those of chronic disease and cachexia and include nonregenerative anemia and hypoalbuminemia. Bone marrow examination may reveal clonal expansion of lymphoid precursor cells.



Diagnosis


Lesions seen at necropsy include homogeneous white to tan masses that bulge on the cut surface. They may be small or large. Less commonly, diffuse paleness of the reticuloendothelial organs is noted. Microscopic examination of these tissues reveals infiltrates of abnormal cells of the lymphocyte line.



Prevention


Avoiding exposure to the bovine leukemia virus and restricting the use of instruments to one animal between cleaning procedures may help prevent the spread of lymphosarcoma. In most animals, however, this neoplasm appears to develop spontaneously.



Failure of Passive Transfer



Pathogenesis


Lambs and kids are born with functional lymphocytes that are capable of producing endogenous immunoglobulin. These cells develop the ability to respond to foreign antigens in the fetus at approximately 80 days of gestation. Because of a lack of in utero exposure, however, basal concentrations of immunoglobulin are low at birth. These cells therefore respond too sluggishly to new challenges to provide an adequate defense against acute infection for approximately the first 6 weeks of life. Additionally, as with other ruminants, no transplacental passage of immunoglobulin to fetal sheep and goats occurs. Lambs and kids depend on intestinal absorption of ingested colostral antibodies to provide a ready supply of immunoglobulin and allow opsonization of pathogens for the first months of life.


Adequate passive transfer requires delivery of a sufficient quantity of good-quality colostrum into the gastrointestinal tract, as well as adequate absorption of antibodies from the colostrum into the blood. In general, meeting this requirement is left to chance: The quality of the colostrum, amount ingested, and adequacy of absorption are rarely monitored. Problems in colostral quality can arise with young, sick, undernourished, and poorly vaccinated dams. Problems in availability can arise with antepartum leakage or nursing by another lamb or kid. Problems in ingestion can arise with weak or sick neonates, competition with other lambs or kids, and separation of the neonate from the dam. Problems in absorption can arise with weakness, sickness, hypothermia, hypoxemia, dehydration, previous exposure of the gut to protein, delay in ingestion, and other factors that affect gut function in the neonate. Sheep and goats are especially prone to many of these causes of failure of passive transfer because of their tendency to give birth to multiple offspring per gestation; the earliest-nursing, most vigorous offspring may ingest more than their share of colostrum.


As extrapolated from equine research, a finding of 800 mg/dL of immunoglobulin in the plasma of a 1-day-old lamb or kid is considered indicative of adequate passive transfer. No research has been done to show that this particular concentration is significantly protective in small ruminants, and probably of greater importance than any bulk amount is absorption of immunoglobulin against specific opportunistic and primary pathogens. Moreover, this amount should be considered minimally acceptable—most healthy small ruminant neonates achieve immunoglobulin concentrations that are 50% to 200% higher.


In addition to immunoglobulin, colostrum also contains large quantities of fat-soluble vitamins that do not cross the placenta. The most important of these are vitamins A, D, and E, which are important in bone development and the immune or inflammatory response. Neonates that have not ingested enough colostrum are likely to be deficient in these vitamins.



Diagnosis


A diagnosis of failure of passive transfer can be deduced from the history if the neonate is known not to have ingested colostrum in the first day of life or the dam is known not to have produced colostrum. Owners occasionally evaluate lambs or kids for adequate intake by picking up the animal and holding it at ear level, while carefully cradling the head and neck, and then shaking the abdomen in order to hear milk in the abomasum. A presumptive diagnosis can be made if the neonate shows signs of undernourishment or sepsis in the first few days after birth. A definitive diagnosis can be made by direct laboratory measurement (radioimmunoassay) of immunoglobulin concentrations. Numerous semiquantitative methods of estimating immunoglobulin are available, including various agglutination (glutaraldehyde) and precipitate assays (sodium sulfate) and measurement of blood protein fractions (Chapter 8; see Table 8-6). Measurement of total protein in a well-hydrated animal by means of a hand-held refractometer may be used as a quick screen. A total protein of 5.5 to 6 mg/dL or greater usually is suggestive of successful transfer of colostral antibodies in a normally hydrated neonate. These methods may be relied on to give an overall flock assessment of adequacy of passive transfer, but they are rarely accurate enough to provide definitive information on individual animals23 (see Chapter 8).



Treatment


Failure of passive transfer is not in itself pathologic, but it greatly increases the neonate’s susceptibility to infectious diseases. The amount of colostrum absorbed across the gut decreases with time, especially in animals that have been ingesting other proteins (e.g., the casein in milk); it also decreases with illnesses that decrease gastrointestinal function. Sufficient immunoglobulin likely cannot be absorbed more than 24 hours after birth. Therefore oral colostrum is the best treatment in the immediate postpartum period in still-healthy neonates. Same-species colostrum is best: Hemolysis has been reported in lambs receiving cattle colostrum. To make up for complete failure, approximately 5% of the neonate’s body weight by volume of colostrum (or around 1.25 g of immunoglobulin/kg of body weight) should be administered on two separate occasions, 4 to 12 hours apart. Colostral substitutes generated from slaughterhouse blood are becoming available, but their absorption and efficacy remain largely untested. After the window for immunoglobulin absorption has closed, plasma administered by the intravenous or intraperitoneal route is the best way to raise the neonate’s blood immunoglobulin concentrations. Adult donor plasma contains approximately 2.5 to 3.5 g of immunoglobulin/dL, so a volume equivalent to 10% of body weight is necessary to achieve similar concentrations as with normal passive transfer. If plasma is used instead of colostrum, administration of vitamins A, D, and E also may be beneficial.


If colostrum and plasma are unavailable or cost-prohibitive, “closing” the gut as quickly as possible with milk, maintaining high standards of hygiene, and possibly administering prophylactic antibiotics offer the greatest prospects for preventing infectious disease. Vaccination of the neonate or the administration of antitoxin hyperimmune serum should not be considered protective but may be of value.



Prevention


Ensuring colostral quality is best done through good nutrition, health care, and vaccination of dam (see Chapters 2 and 19). Administration of vaccines 6 weeks before parturition, followed in 2 weeks with a booster, provides the highest quantity of protective immunoglobulin in the colostrum. Antepartum leakage is rarely the problem in small ruminants that it is in horses and cattle. However, in a flock or herd environment, still-pregnant dams may steal babies from other sheep or goats. To prevent such theft and the resultant loss of colostrum by the “adopted” neonate, owners may choose to keep pregnant animals separate from those that have already delivered. If complete separation is not possible, the dam and her offspring should be allowed to bond with each other in a private pen (“jug” or “crate”) for at least 24 hours before being placed back with the flock. Clipping excessive wool or mohair from around the perineal area and udder before lambing or kidding, expressing the teats to ensure they are not plugged, and having extra colostrum available when pregnant females are placed in jugs or crates are other good preventive measures.



Neonatal Sepsis



Pathogenesis


Sepsis is the condition resulting from systemic bacterial infections or toxemia. Most systemic bacterial infections are caused by opportunistic infections in immunocompromised animals or the overwhelming of a competent immune system with massive challenge. Rarely, small numbers of aggressive primary pathogens are the cause. The most common cause of immune dysfunction in neonates is failure of passive transfer. Less common causes include nutritional deficiencies (notably in selenium, copper, or vitamin E), stress, and other illnesses.


Bacteria enter the body through the gastrointestinal or respiratory tract or through a break in the skin (e.g., umbilicus, castration site, docked tail, wound). The role of the umbilicus is usually overemphasized over the other, more common routes. Bacteria proliferate locally and either enter the circulation or produce toxins that enter the circulation. After entering the bloodstream, bacteria seed various body sites, including the lungs, kidneys, liver, central nervous system, joints, umbilicus, lymphoid tissue, and body cavities. Toxins tend to damage blood cells, vascular endothelium, and various organ tissues. Overwhelming bacteremia or toxemia usually is fatal; less severe disease is associated with localization of the bacteria to one or more sites of chronic infection such as the umbilicus, lymph nodes, organ abscesses, and joints. The greater the immune responsiveness of the animal, the more likely it is to prevent invasion and clear the infection.


The major opportunistic causes of neonatal sepsis include most Escherichia coli, Streptococcus, Actinomyces (Arcanobacter), and other organisms (often gram-negative enteric bacteria). Most of these organisms are normal inhabitants of the ruminant gastrointestinal tract or soil and therefore are likely to be found in the highest concentrations around areas on farms/ranches with the poorest hygiene. The major primary causes of neonatal sepsis include some strains of E. coli, Salmonella dublin or Salmonella typhimurium, and Erysipelothrix rhusiopathiae. These organisms may be associated with illness in adults and outbreaks in neonates despite good nutrition and hygiene and adequate passive transfer.



Clinical Signs


The clinical signs of acute sepsis are the same as those of shock. Fever is present in the most acute phase but is transient, and the absence of fever should not be taken as evidence against the presence of bacterial infection. Hypothermia often is present in advanced cases. Other common clinical signs include obtundation, anorexia with a weak suckle reflex, cold extremities, dry or tacky mucous membranes with purple-blue discoloration (buccal) or enlarged and engorged blood vessels (sclerae), tachycardia, prolonged tenting skin, and poor filling of the jugular veins. Diarrhea, swollen joints, tachypnea, and specific neurologic abnormalities may be present if the pertinent organs are affected.



Diagnosis


A presumptive diagnosis can be made by observation of the previously described clinical signs in a neonate. Other disorders that can produce these signs include hypothermia, hypoxemia, congenital cardiovascular or nervous system anomalies, and starvation. These other disorders often coexist with sepsis as predisposing factors or complications of the infectious disorder. Clinicopathologic data that support a diagnosis of sepsis include evidence of failure of passive transfer, hyperfibrinogenemia, and left shift of the leukogram, particularly when neutropenia, toxic changes to neutrophils, or myelocytes and metamyelocytes are present. Serum biochemical analysis may be helpful in assessing overall condition.23 Definitive diagnosis of sepsis is achieved by isolating the bacteria. Blood culture or postmortem internal organ culture is the best diagnostic tool for acute, untreated bacteremia. Findings in aspirates of abscesses or infected joints are more accurate if sepsis is long-standing, particularly if the animal has been treated with antibiotics.



Treatment


Treatment for neonatal sepsis is most rewarding when initiated early in the infection. Although cost and residues are always a concern when treating young food animals, their small size combined with a long time interval until slaughter or milk production gives the clinician greater leeway in choosing appropriate antimicrobial agents. Because both gram-positive and gram-negative infections are possible, broad-spectrum coverage through single antibiotics or combinations of them is preferred (ceftiofur, 1 to 2.2 mg/kg given intramuscularly [IM] once or twice a day). Treatment should be continued for at least 5 days to ensure clearance of the infective organism. Nonsteroidal antiinflammatory drugs (NSAIDs) also are beneficial in their antipyretic, antiinflammatory, and anti-endotoxin effects (e.g., flunixin meglumine, 1 to 2 mg/kg given intravenously [IV] or IM [of note, although flunixin meglumine is labeled for intramuscular use, myositis has been reported in some species when the drug is administered by this route]).


If the neonate is severely dehydrated or obtunded, fluid treatment should be initiated. Because septic neonates often are deficient in immunoglobulin as a result of failure of passive transfer or consumption of antibodies fighting the infection, plasma transfusions often are beneficial. Plasma should come from the same species; whole blood can be used in an emergency situation. Adverse reactions are rare.



Prevention


Methods to improve colostral quality and passive transfer are helpful in preventing sepsis. Decreasing overcrowding, separating neonates from most adult stock (except their dams), and decreasing fecal and soil contamination of facilities will decrease the amount of bacterial challenge. Sanitizing common equipment and minimizing contamination of tail docking and castration sites also are important. Dipping the umbilicus is of questionable importance and probably is unnecessary in well-managed, clean flocks. The procedure is harmless, however, and provides an opportunity to examine the newborn, so current recommendations include dipping the umbilicus with dilute iodine or chlorhexidine solutions.23



Uncomplicated Neonatal Diarrhea



Pathogenesis


Uncomplicated diarrhea may be caused by viral, bacterial, or protozoal pathogens. These organisms differ from the agents of complicated diarrhea in that they do not invade beyond the gut wall or result in systemic toxemia (see Chapter 5).


The net result of such an infection is that a large volume of isotonic intestinal fluid is lost into the bowel with the unabsorbed ingesta. If enough fluid and electrolytes are lost, dehydration and metabolic acidosis induce systemic clinical signs similar to those seen in complicated diarrhea. In goats, this clinical entity is one component of the floppy kid syndrome.



Clinical Signs


Profuse, watery diarrhea without fever is the hallmark clinical sign. With severe dehydration or acidosis, affected lambs and kids become weak and dull and lack appetite. Mucous membranes become tacky, and skin tenting times are prolonged. Shock signs may develop. Physical assessment often has to take the place of clinicopathologic analysis in lambs and kids.


Mild, nonclinically complicated diarrhea is characterized by profuse diarrhea with minimal systemic signs. The affected animal is bright and alert, with minimal skin tenting, and can stand and eat readily, with a strong suckle reflex. It is less than 5% dehydrated, with a blood pH of 7.35 to 7.50 and a bicarbonate deficit of 0 mEq/L (see also Chapter 3).


Moderate uncomplicated diarrhea is characterized by profuse diarrhea in a dull but responsive animal. Skin tenting is prolonged, but eye luster is normal. The affected sheep or goat is able to stand and eat, but eats slowly and has a weak suckle reflex. The head typically is held down. It is 5% to 7% dehydrated, with a blood pH of 7.10 to 7.25 and a bicarbonate deficit of 5 mEq/L.


Severe uncomplicated diarrhea is characterized by profuse diarrhea. The affected sheep or goat is dull and minimally responsive, with a very long skin tent time and dull, sunken eyes. It can stand only with assistance and prefers to stay in sternal recumbency with its head up. The animal eats very slowly, if at all, and has a minimal suckle reflex. It is 8% to 10% dehydrated, with a blood pH of 6.90 to 7.10 and a bicarbonate deficit of 10 mEq/L.


Very severe uncomplicated diarrhea is characterized by profuse diarrhea and profound weakness. The animal’s skin remains tented for more than 1 minute, and its eyes are very sunken and dull. It is nonresponsive with no suckle response. It is unable to maintain sternal recumbency lying on its side instead. The animal is 10% to 12% dehydrated, with a blood pH of 6.8 to 7.0 and a bicarbonate deficiency of 15 to 20 mEq/L.



Clinical Pathology


The leukogram should be normal or show abnormalities compatible with stress. Serum biochemical or blood gas analysis may reveal evidence of intestinal electrolyte loss (hyponatremia, hypochloremia, metabolic acidosis) and dehydration (hyperalbuminemia, azotemia).



Diagnosis


A presumptive diagnosis may be based on the characteristic clinical signs and exclusion of causes of complicated diarrhea (“scours”). Response to conservative treatment also is supportive of this diagnosis. Identification of the specific causative agent is less important than proper treatment of infected animals. To identify the causative agent, feces should be examined by electron microscopy to identify viruses, by culture to determine a bacterial cause, and by light or fluorescence microscopy after sugar flotation, acid-fasting, auramine, or fluorescent antibody staining for Cryptosporidium parvum.



Treatment


The immediate goals of treatment are rehydration, replacement of lost electrolytes, and restoration of acid-base balance. Less immediate goals are provision of nutrition and replacement of ongoing losses. The aggressiveness of treatment is dictated by the severity of the condition, as well as economic considerations.24



1. Rehydration: Calculate the percent dehydration and use to calculate fluid requirement.


Example: 10% dehydration in a 3-kg lamb: 0.1 × 3 kg × 1 kg/L = 0.3 L, or 300 mL.


2. Replace lost electrolytes: Sodium, chloride, bicarbonate, and potassium are lost roughly in proportion to extracellular fluid; replace in roughly the same proportions (except for providing more bicarbonate and less chloride; see next step). Replace with fluid that is similar in composition to extracellular fluid.


3. Restore the acid-base balance: Estimate bicarbonate deficit by blood gas analysis (24 mEq, as measured) or physical assessment. Then calculate the whole body deficit.


Example: Assessment suggests a deficit of 16 mEq/L bicarbonate in a 3-kg, comatose lamb with prolonged skin tenting (0.5 is the multiplier for extracellular fluid in a neonate): 0.5 × (16 mEq/L) × 3 kg × 1 kg/L = 24 mEq bicarbonate.


Therefore the immediate goal is to provide 300 mL of fluid and 24 mEq of bicarbonate to this lamb in a formulation that resembles normal extracellular fluid (ECF). Fluids can be given by various routes:



Oral




• Advantages: Oral fluids are inexpensive (nonsterile) and easy to give. They are less likely to cause fatal arrhythmias or neurologic disease than intravenous fluids.


• Disadvantages: An animal receives a maximum of its gastric volume (5% of body weight), and good gastric motility is required. Oral fluids may not be well absorbed by a damaged gut. Absorption also is slow.



Intravenous




• Advantage: This method allows rapid correction of all deficits, even in moribund animals.


• Disadvantages: It is expensive (sterile), requires venous access, and can rapidly lead to overcorrection.



Subcutaneous




• Advantages: This method does not require venous access or good gut motility.


• Disadvantages: It is expensive (sterile), and the fluids may not be well absorbed in very dehydrated animals. Absorption is not as quick as by intravenous administration. Animals should be given only hypotonic or isotonic fluids.



Intraperitoneal




• Advantages: This method does not require venous access or gut motility. Fluids are absorbed quickly by this route.


• Disadvantages: It is expensive (sterile) and can cause peritonitis. Isotonic fluids are best used in this route. Only a limited volume can be given.


In general, lambs and kids with good appetites (especially those being fed by bottle) and those that have recently become inappetent (including those being fed by tube or bottle) may be treated with oral fluids, but animals with poor appetite coupled with severe dehydration should receive intravenous or subcutaneous fluids. Subcutaneous fluids are most useful as an adjunct: Another 300 or 400 mL or so can be given to a neonate that has already received an intravenous bolus, to provide a prolonged effect. If oral fluids have not produced an improvement within 2 to 4 hours, intravenous treatment should be strongly considered.


Many good commercial oral fluids are available. These contain electrolytes (sodium similar to plasma), an alkalinizing agent (bicarbonate, propionate, acetate, citrate; most good ones have approximately 80 mEq/L of base), and glucose or glycine to slow gastric emptying and aid in sodium absorption. The amount of carbohydrates varies, being higher in “high-energy” solutions. Less carbohydrate is needed in less severely affected animals because they are less likely to have severe hyponatremia. Fluids to be avoided include medicated milk replacers and unbuffered saline solutions.


Intravenous treatment should be provided with a sterile commercial product. Such preparations typically contain 25 to 30 mEq/L of base. Additional sodium bicarbonate solution or powder can be added (12 mEq of bicarbonate/g of powder, or 1 mEq/mL of 8.4% solution) to replace the base deficit. The bicarbonate deficit should be replaced gradually, over 4 hours, to avoid the development of neurologic abnormalities.


After deficits are replaced, the following continued treatments and adjuncts may be considered:



1. Continued administration of fluids (oral rather than intravenous if possible) to replace ongoing losses (see Chapter 3):


• A volume equal to 5% of the body weight per feeding can be given orally; the number of feedings can be increased from two (normal) to three to six a day. After 24 hours, less hypertonic fluids can be used.

• Intravenous fluids can be continued at twice the maintenance fluid rate until appetite is restored.

• More bicarbonate may be necessary.

2. Consideration of addition of milk to the treatment regimen:


• Milk has more energy but fewer electrolytes per unit of fluid.

• Milk can be used for up to half of the feedings:

Lambs fed milk lose less weight with scours.

Free water helps prevent hypernatremia.

• Milk should not be mixed with electrolytes because they inhibit curd formation (although acetate is allegedly safe).

• Milk may exacerbate diarrhea in the early stage:

Large intestine fermentation leads to osmotic diarrhea and further fluid loss. Withholding milk for 24 hours may help, but longer delays lead to cachexia.

• Milk is a good potassium source.


Other Causes of Weakness and Depression in Neonates


Ruling out infectious causes of depression and weakness is difficult, and clinicians often do well to assume that an infectious disease is contributing to clinical signs when making treatment decisions. However, a number of noninfectious systemic disturbances also can depress neurologic and muscular function. Successful treatment often requires identification and correction of each of these disturbances. Among the more common abnormalities leading to depression in neonates are hypoxemia, metabolic or respiratory acidosis, hypothermia, hyperthermia, hypoglycemia, dehydration, azotemia, and some electrolyte imbalances.


Hypothermia and hyperthermia can easily be diagnosed by measuring body temperature with a rectal thermometer. Hypothermia is far more common and can result from weakness, shock, and environmental stress. Cold, windy weather or tube feeding with cold milk replacer or fluids can lead to a rapid drop in core body temperature, especially in neonates that are small or weak or have been inadequately licked off or were rejected by their dams. Strong, vigorous neonates usually are protected by heat produced during muscular activity and are able to seek food and shelter. Clinical signs appear when the rectal temperature drops to 98° F (36.7° C) or below. Protection from wind and cold such as with an individual ewe jug or pen, heat lamps (positioned far enough away so as not to burn the neonate), hot water bottles, blankets, and administration of warm fluids is helpful in treating and preventing hypothermia. Shearing the ewe before lambing is of value because it forces the ewe to seek shelter. If this management technique is used, care should be taken to avoid inducing severe hypothermia in the dam.


Environmental hyperthermia is much less common than fever in neonates. Therefore treatment for infectious diseases in young animals with high temperatures usually is warranted. Providing cool shelter with good ventilation, minimizing stressful events, ensuring adequate fluid intake, and shearing the adults are the best defenses against environmental heat stress.


Hypoglycemia also is easy to diagnose with the aid of an inexpensive, portable glucose meter. Lambs and kids typically develop hypoglycemia under the same circumstances as those leading to hypothermia. Administering 50 mL/kg of dextrose (approximately 3.5 fl oz/lb, or 5% of body weight) in warm milk replacer or 1 mL/kg of 50% dextrose, by either the intravenous or oral route (diluted to 5% dextrose), should provide ample energy to correct hypoglycemia. Intravenous administration may be necessary if gut motility is absent. Follow-up treatment may be necessary if the neonate does not regain its appetite.


Except during severe conditions, normal lambs and kids should be able to maintain normal body core temperature. They should therefore be examined for an underlying disorder if they exhibit signs of hypothermia or hyperthermia. Clinicians and owners should not assume that warming and feeding a cold, weak neonate will always correct the problem.


Hypoxemia is much more difficult to diagnose. Portable blood gas meters for arterial analysis and radiography units for thoracic imaging are available but are still not in common use in small ruminant practice. For those reasons, hypoxemia usually is underdiagnosed. Hypoxemia can result from prematurity or dysmaturity, infection, depression or weakness (decreased ventilation), meconium aspiration, bullous emphysema, hernias, and other thoracic fluid or tissue masses. It is likely to be a contributing factor in illness and death in most weak neonates younger than 3 days of age. Such animals benefit from the provision of supplemental oxygen, either through a nasal insufflation tube or by oxygen tent. In addition to its direct effect on general well-being and behavior/attitude, hypoxemia at birth leads to poor gut function and subsequent poor colostral absorption. Many animals that exhibit failure of passive transfer and subsequent sepsis had a previous bout of hypoxemia.


Azotemia, metabolic acidosis, and electrolyte imbalances are difficult to diagnose without clinicopathologic analysis. Therefore these problems are best treated in animals showing signs of dehydration with the administration of a balanced, physiologic electrolyte solution. Metabolic acidosis usually is accompanied by either obvious evidence of bicarbonate loss (diarrhea) or severe dehydration. However, neither of these conditions is present with floppy kid syndrome. This descriptive title is applied to muscle weakness, anorexia, and depression in kids observed in the first 2 weeks of life. By its strictest definition, floppy kid syndrome refers to metabolic acidosis with a high anion gap without dehydration or any known cause in young kids that were normal at birth. A variety of disorders and conditions have been proposed as the cause of metabolic acidosis without dehydration, including intestinal fermentation of milk in well-fed kids with subsequent absorption of volatile fatty acids, transient neonatal renal tubular acidosis, and lactic acidosis secondary to toxic impairment of cardiovascular function. Overgrowth of C. perfringens type A often is suggested as a source of the toxin. With a high anion gap, a pathologic condition that leads to overproduction of an organic acid is more likely than one that leads to bicarbonate loss. The disease can occur in individual animals or in outbreaks; although parity of the dam and number of offspring have not been associated with this metabolic disturbance, aggressively feeding kids are more likely to suffer from milk fermentation or clostridial overgrowth. An infectious etiology appears to be more likely in herds displaying an increased incidence of this metabolic disturbaces as the kidding season progresses. The disease also is reported to be more common in meat goats than in dairy goats. The prevalence can vary tremendously from year to year in a single flock or region. A similar disease has been reported in calves and llama crias, and lambs also are likely to be susceptible under the right conditions.


Because blood gas analysis and exclusion of other diseases often are impractical, the term floppy kid syndrome frequently is used by owners to refer to any kid that is weak and does not have an overt, organ-specific sign (e.g., diarrhea). Different pathologic processes are grouped together by their common clinical endpoint (as with “thin ewe syndrome”), and the veterinarian is charged with determining the etiology in a specific flock. Most possible causes are found in the previous list of conditions that cause weakness and depression in neonates. Among these entities, sepsis and hypoxemia are the most important items and therefore also must be considered important causes of possible floppy kid syndrome. Treatment and prevention of floppy kid syndrome currently follow the same lines as for treatment and prevention of neonatal sepsis or enteritis. Spontaneous recovery of animals with floppy kid syndrome may occur. However, in valuable kids, quick assessment of blood chemistry and base deficits will allow requisite correction of electrolyte and blood pH abnormalities with 1.3% sodium bicarbonate.25



References



1. Morris D.D. Anemia. In Smith B.P., editor: Large animal internal medicine, ed 2, St Louis: Mosby, 1996.


2. Vatta A.F., et al. Testing for clinical anaemia caused by Haemonchus spp. in goats farmed under resource-poor conditions in South Africa using an eye colour chart developed for sheep. Vet Parasitol. 2001;99:1-14.


3. Kaplan R.M., et al. Validation of the FAMACHA eye color chart for detecting clinical anemia in sheep and goats on farms in the southern United States. Vet Parasitol. 2004;123:105-120.


4. Reynecke DP, et al: Validation of the FAMACHA eye colour chart using sensitivity/specificity analysis on two South African sheep farms, Vet Parasitol (online postprint article), doi:10.1016/j.vetpar.2009.08.023: http://hdl.handle.net/2263/11638. Accessed November 6, 2009.


5. Moors E., Gauly M. Is the FAMACHA chart suitable for every breed? Correlations between FAMACHA scores and different traits of mucosa colour in naturally parasite infected sheep breeds. Vet Parasitol. 2009;166:108-111.


6. Selim H.M., et al. Rumen bacteria are involved in the onset of onion-induced hemolytic anemia in sheep. J Vet Med Sci. 1999;61:369-374.


7. McPhail D.B., Sibbald A.M. The role of free radicals in Brassica-induced anaemia of sheep: an ESR spin trapping study. Free Radic Res Commun. 1992;16:277-284.


8. Smith R.H. Kale poisoning: the Brassica anaemia factor. Vet Rec. 1980;107:12-15.


9. Van Kampen K.R., James L.F., Johnson A.E. Hemolytic anemia in sheep fed wild onion (Allium validum). J Am Vet Med Assoc. 1970;156:328-332.


10. Maiorka P.C., et al. Copper toxicosis in sheep: a case report. Vet Hum Toxicol. 1998;40:99-100.


11. Soli N.E., Froslie A. Chronic copper poisoning in sheep. I. The relationship of methaemoglobinemia to Heinz body formation and haemolysis during the terminal crisis. Acta Pharmacol Toxicol (Copenh). 1977;40:169-177.


12. Todd J.R. Chronic copper toxicity of ruminants. Proc Nutr Soc. 1969;28:189-198.


13. Hidiroglou M., Heaney D.P., Hartin K.E. Copper poisoning in a flock of sheep. copper excretion patterns after treatment with molybdenum and sulfur or penicillamine. Can Vet J. 1984;25:377-382.


14. Decker M.J., Freeman M.J., Morter R.L. Evaluation of mechanisms of leptospiral hemolytic anemia. Am J Vet Res. 1970;31:873-878.


15. Smith B.P., Armstrong J.M. Fatal hemolytic anemia attributed to leptospirosis in lambs. J Am Vet Med Assoc. 1975;167:739-741.


16. Overås J. Studies on Eperythrozoon ovis infection in sheep, Acta Vet Scand Suppl. 1969;28(Suppl 28):1.


17. Sutton R.H. Eperythrozoon ovis—a blood parasite of sheep. N Z Vet J. 1974;18:156-164.


18. Sutton R.H., Jolly R.D. Experimental Eperythrozoon ovis infection of sheep. N Z Vet J. 1973;21:160-166.


19. Neimark H., Hoff B., Ganter M. Mycoplasma ovis comb. nov. (formerly Eperythrozoon ovis), an epierythrocytic agent of haemolytic anaemia in sheep and goats. Int J Syst Evol Microbiol. 2004;54:365-371.


20. Hornok S., et al. Molecular characterization of two different strains of haemotropic mycoplasmas from a sheep flock with fatal haemolytic anaemia and concomitant Anaplasma ovis infection. Vet Microbiol. 2009;136:372-377.


21. Nappert G., et al. Bovine colostrum as a cause of hemolytic anemia in a lamb. Can Vet J. 1995;36:104-105.


22. Suttle N.F., et al. Heinz body anaemia in lambs with deficiencies of copper or selenium. Br J Nutr. 1987;58:539-548.


23. Koterba A.M., House J.K. Neonatal infection. In Smith B.P., editor: Large animal internal medicine, ed 2, St Louis: Mosby, 1996.


24. Naylor J.M. Neonatal ruminant diarrhea. In Smith B.P., editor: Large animal internal medicine, ed 2, St Louis: Mosby, 1996.


25. Rowe JD, East NE: Floppy kid syndrome (metabolic acidosis without dehydration in kids), Proceedings of the 1998 Symposium on the Health and Disease of Small Ruminants Western Veterinary Conference, Las Vegas, Nev, 1998.



Disease Caused by Tissue-Invading Clostridia


Tissue-invading clostridia are large, straight, gram-positive rods that are 3 to 10 μm in length. C. perfringens and C. haemolytica are smaller bacteria, and Clostridium novyi, Clostridium chauvoei, and Clostridium septicum are larger. The bacteria grow best under anaerobic conditions and produce waste gases. Clostridia bear spores, which may be the only viable form in soil. Identification of these spores within bacteria on microscopic examination is useful to identify clostridia. Spores in C. perfringens are central and do not affect the shape, whereas most other species have the spore toward one end and appear slightly club-shaped.


Clostridia cause infectious, noncontagious disease. The bacteria inhabit the intestinal tract and are present in the feces of many healthy animals. Small numbers of organisms in their dormant spore form also may reside in tissues such as liver and skeletal muscle. They can be isolated from soil, where most are thought to have short life spans. Soil concentrations are highest in locations recently contaminated with ruminant feces, especially crowded, overused facilities such as feedlots and lambing sheds. Environmental contaminations are associated with cool, damp times of the year such as late winter and spring.


The concentration of organisms and their toxins found in the feces, gut contents, and internal organs of most adult ruminants usually is small. Competition and peristalsis prevent overgrowth in the gut and aerobic conditions prevent overgrowth in other tissues in live animals. However, rapid overgrowth and tissue invasion ensue after death, making rapid postmortem examination essential to ascertain whether clostridial organisms are responsible for the death.


Pathogenic clostridial organisms all produce heat-labile protein exotoxins. Most make a variety of toxins, and the relative contribution of each toxin to the disease state is not known. The major exotoxins of C. perfringens are alpha, a phospholipase that lyses mammalian cells; beta, a trypsin-labile necrotizing toxin; epsilon, a trypsin-activated necrotizing toxin; and iota, another trypsin-activated necrotizing toxin. Toxin production is used to classify C. perfringens organisms according to type. All five types of C. perfringens make alpha toxin. Types B and C also make beta toxin (with B making epsilon toxin as well), type D makes epsilon toxin, and type E makes iota toxin. Because the necrotizing toxins cause more prominent lesions than alpha toxin, they are used to characterize diseases caused by C. perfringens infection with types other than A. Other tissue-invasive clostridial organisms make toxins similar to those produced by C. perfringens, in addition to various other necrotizing and hemolyzing toxins. In many instances these toxins can be chemically altered to produce antigenic toxoids.1–4




Enteric Infections



Pathogenesis


Enteric clostridial organisms are thought to proliferate under conditions of decreased peristalsis and poor ruminal and abomasal function. Weather and handling stresses, feed changes, and an overabundance of high-energy feeds are thought to promote overgrowth. Milk, bakery products, and cereal grains are the most common high-energy feeds associated with outbreaks. Toxin production occurs with overgrowth and precipitates disease. Other enteric infections that disrupt the mucosal border may increase systemic absorption of toxins.


C. perfringens type A occurs worldwide and is the most common type of this species isolated from soil. It causes “yellow lamb disease” in younger animals, a condition reported much more commonly in sheep than in goats. Risk factors for infection have not been established. This disease occurs most commonly in lambs 2 to 6 months old. Under favorable conditions, the organisms proliferate and cause a corresponding increase in alpha toxin production. The alpha toxin causes minor gastrointestinal lesions and is absorbed across the gut wall to cause hemolysis and vasculitis. The clinical course usually is less than 24 hours (see Chapter 5).



Clinical Signs


The clinical signs include weakness, depression, fever, icterus, anemia, hemoglobinuria, tachypnea, and terminal recumbency. Laboratory evaluation reveals evidence of intravascular hemolysis. Necropsy reveals evidence of hemolysis, hyperemic intestines, and multifocal internal petechial hemorrhages. Positive diagnosis is based on identification of the alpha toxin and the absence of other toxins on testing by newer enzyme-linked immunosorbent assays (ELISAs) or older live animal assays. Morbidity in a flock is lower than for many of the other enteric clostridial diseases, but the mortality rate is very high.


Adult animals also are susceptible to hemolytic disease and vasculitis caused by C. perfringens type A infection. The organism has been isolated from sites distant from the infection, including muscle and the mammary gland. Fatal abomasitis and rumenitis in neonates and juveniles also have been blamed on C. perfringens type A, but the rapid postmortem proliferation of the organism makes substantiation of this claim difficult.



Clinical Pathology


The most characteristic clinicopathologic change is neutrophilic leukocytosis with a left shift. Other evidence of systemic toxemia (metabolic acidosis, azotemia, increases in liver and muscle enzymes) also may be seen.



Treatment


Administration of antibiotics such as penicillin and Clostridium antitoxin is the mainstay of treatment, although animals may die acutely before therapies can be instituted.



Prevention


A conditionally licensed toxoid against the clostridial alpha toxin is available for cattle in the United States. Prevention efforts should focus on environmental hygiene and avoiding gut conditions favorable for proliferation of the organism. Because this type appears to survive better in soil than other types, preventing ingestion of soil may be important in preventing disease.



Clostridium perfringens Type B and C Disease


C. perfringens types B and C cause very similar diseases called lamb dysentery and hemorrhagic enterotoxemia, respectively. Both lambs and kids can be affected. With both diseases, the beta toxin is an important pathophysiologic factor, and inactivation of this toxin after maturation of pancreatic trypsinogen secretion effectively limits the susceptible population to neonatal animals. Older animals may become susceptible as a result of overwhelming infection or trypsin inhibition by some soy and sweet potato products. The reported geographic range of both neonatal diseases is limited (type B to the United Kingdom and South Africa and type C to the United Kingdom and North America), even though infection with C. perfringens type C appears to occur worldwide.


The diseases initially affect lambs and kids younger than 3 days of age, with illness occasionally occurring in older lambs. Because of management practices in this age group and age-related vulnerability, fecal contamination of teats, hands, and equipment that enter the mouths of the neonates (orogastric tubes, nipples) is a major cause of infection. Severely affected animals or those at the beginning of an outbreak usually are found dead. Less acutely affected animals expel yellow, fluid feces that may contain brown flecks of blood and show splinting of the abdomen, especially when handled, along with signs of colic and feed refusal. The clinical course usually is short, and the disease is almost always fatal. Terminal convulsions and coma occasionally are noted, especially in outbreaks in the United States. Postmortem examination reveals small hemorrhagic ulcers in the small intestine with type B infection and diffuse reddening with hemorrhage and necrosis of the abomasum and the entire intestine with type C infection. Animals that die very rapidly may exhibit minimal or no gross abnormalities of the intestine.


C. perfringens type C in older sheep causes the disease known as “struck.” Temporary suppression of pancreatic trypsin production may be important in pathogenesis. Affected animals usually are found dead or with signs of toxemia. Specific antemortem signs of gastrointestinal disease are rare. Postmortem changes include neutrophilic leukocytosis with a left shift. Additional evidence of systemic toxemia (metabolic acidosis, azotemia, increases in liver and muscle enzymes) also may be seen.



Diagnosis


Diagnosis of these diseases is made by identification of characteristic lesions and positive toxin assays. Because the beta toxin is very labile, negative toxin assays are less significant than negative assays for presence of other tissue-invading clostridia.



Treatment


If the infection is identified early in the disease course, antibiotics such as penicillins and Clostridium antitoxin may be of benefit. Fluids and antiinflammatory agents may be indicated as well. Usually the condition is not recognized until the animal is dead or dying.

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