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Secondary Immunodeficiencies of Horses
IMMUNOLOGY
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SECONDARY IMMUNODEFICIENCIES OF HORSES Debra C. Sellon, DVM, PhD
Immunodeficiencies are disorders resulting from the absence ' or failure of function of one or more components of the immune system. Secondary or acquired immunodeficiencies occur as a consequence of extrinsic or environmental conditions. The commonest secondary immunodeficiency of horses is failure of passive transfer of immunoglobulin in neonatal foals. Other causes include immunodeficiency or immunosuppression secondary to an underlying disease process (e.g., infection, malnutrition, neoplasia), irradiation, or drug therapy (e.g., corticosteroids). Regardless of cause, immunodeficiency disorders are characterized by an increased susceptibility to infection. Foals with failure of passive transfer are at increased risk for septicemia or other bacterial infections. Adult horses with acquired immunodeficiencies often present with clinical signs of recurrent or persistent infections, poor response to appropriate antimicrobial therapy, or infection with normally nonpathogenic organisms. In generat defects in humoral immunity predispose to infection with pyogenic bacteria, whereas deficiencies in cell-mediated immunity predispose to overwhelming infection by organisms that are generally considered nonpathogenic in immune-competent animals (e.g., Candida albicans, Cryptosporidium spp., adenovirus). Often the acquired immunodeficiencies affect both humoral and cell-mediated immunity.
From the Department of Veterina~y C'linical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington
VETERINARY CLINICS OF NORTH AMERICA: EQUINE PRACTICE VOLUME 16 • NUMBER 1 • APRIL 2000
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FAILURE OF PASSIVE TRANSFER OF IMMUNOGLOBULINS
Lymphocytes capable of responding to antigenic stimulation are demonstrable in equine fetal tissues as early as day 80 to 100 of gestation, 58, 59 and injected antigens can elicit a humoral response (demonstrable serum IgM and IgG) by day 200 of gestation,49,53 Therefore, foals are essentially immune competent at birth with detectable, but low, quantities of serum immunoglobulin, primarily IgM,66,69 Exposure to pathogenic organisms at birth stimulates a primary immune response, but it takes 10 to 14 days for that response to become protective. 51 ,61 The rate and magnitude of antibody synthesis in response to specific antigenic stimulation in foals has not been compared with that of adult horses 26 but may be diminished because of immature cell-mediated functions at birth.24 During the lag time between exposure to infectious agents and development of a protective immune response, foals can easily be overwhelmed by infectious agents. Passive immunity, acquired from the dam, is essential for protection during the first month of life. Maternal immunoglobulins are not transferred transplacentally in horses because of a diffuse epitheliochorial placenta, which is impermeable to macromolecules, thus preventing the fetus from receiving antibodies or antigens present in maternal circulation. The result is an equine neonate that is born profoundly hypogammaglobulinemic. In the interim between birth and production of adequate spectrum and quantity of specific immunoglobulin by the foal, passive immunity is dependent on ingestion of colostrum. This specialized milk is produced during the last 2 to 4 weeks of gestation as the mammary gland concentrates immunoglobulin from the blood into mammary secretions. 28, 32, 51 Failure of the foal to ingest or absorb sufficient immunoglobulin from colostrum is referred to as failure of passive transfer of immunoglobulin (FPT). FPT is the most important risk factor for localized or systemic bacterial infections in foals during the first month of life and is the commonest immunologic disorder of foals. 38, 50
Production and Absorption of Colostrum
Colostrum is produced in the last few weeks of pregnancy under the influence of estrogens and progesterone and contains components from the mare's blood as well as locally (mammary gland) produced substances. Soluble substances including immunoglobulin,57 cytokines,27 growth factors,21 hormones,21 and enzymes such as lysozyme80 have a positive influence on neonatal immunity and gastrointestinal maturation?9 Cellular components of colostrum include lymphocytes, macrophages, neutrophils, and epithelial cells and are likely to be important in development of local gastrointestinal immunity and modulation of responses to antigens in the newborn,27 Maternal cells in colostrum cross
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the intestinal barrier and are detectable in intestinal mucosa, mesenteric lymph nodes, blood, lungs, liver, and spleen of the neonate. Although colostrum contains a wide variety of soluble and cellular components that are likely to affect immune function in neonates, at this time only colostral immunoglobulins have been linked specifically to passive immunity and susceptibility to infection in the foal.3 8, 50 The predominant immunoglobulin in equine colostrum is IgG (1500-5000 mg/dL) with lesser quantities of IgA (500-1500 mg/dL), IgM (100-350 mg/ dL), and IgG(T) (500-2500 mg/ dL).72 Colostral IgG concentration may exceed 9000 mg/ dL in some mares. 57 Immunoglobulin is preferentially concentrated from blood into the mammary gland secretions beginning 2 to 3 weeks before parturition. 32 Protein concentrations in colostrum decline precipitously in the first 8 hours after parturition as the foal suckles, and immunoglobulin concentrations become negligible within 12 hours when mares are actively suckled. 32, 57, 68 Rate of disappearance of colostral IgG, however, may be influenced by other factors including breed, initial colostral IgG concentrations, or both. 57 IgA is the predominant immunoglobulin in equine milk. Normal foals suckle colostrum within 1 to 3 hours of birth, ~nd maternal antibodies are detectable in the foal's serum within 6 hours. Colostral proteins are absorbed by specialized cells distributed throughout the small intestine. 33 Absorption of large macromolecules is nonselective and occurs by pinocytosis. Absorbed proteins are discharged into the intercellular space, passing into lacteals, and then the systemic circulation. Macromolecular absorption is maximal soon after birth and decreases rapidly with approximately 22% efficiency at 3 hours after birth, decreasing linearly to less than 1% by 20 hours. 3o,31 The cessation of absorption of macromolecules within 24 hours after birth results from a rapid turnover of absorptive cells, possibly triggered by high levels of adrenal corticosteroids at the time of parturition. 33, 55 Foals that receive colostrum within a few hours of birth experience transient proteinuria with urinary protein concentrations peaking by 6 to 12 hours and declining between 24 and 36 hours.29 This urinary protein consists of low molecular weight milk proteins, and the cessation of proteinuria may be a reflection of cessation of macromolecular absorption. 33 Passive antibody concentrations in foals decline rapidly during the first 4 weeks of life, largely because of catabolism of antibody and dilution in the increasing plasma volume of the growing foal.3 3 Transfer of functional IgG into the gastrointestinal tract also may account for partial clearance from the blood and enhanced gastrointestinal immunity.6, 7 The half-life for disappearance of maternal IgG in foals is approximately 20 to 30 days.23. 32, 65 Most maternal immunoglobulins are minimally detectable by 6 months of age, although this depends on the initial concentration of immunoglobulin absorbed. Antibodies to specific infectious agents may persist longer depending on the original colostral concentration and sensitivity of the detection method used. 33 As passive antibody concentrations wane in the foal, autogenous
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immunoglobulin synthesis (active immunity) increases. The result in colostrum-fed foals is a nadir in total serum IgG concentration at approximately 1 to 3 months of age followed by gradually increasing concentrations to adult levels. 61,69 In colostrum-fed foals autogenous IgG is first detectable in serum at approximately 4 weeks of age,32 IgM concentrations reach adult levels at approximately 3 to 5 months of age, whereas IgG and IgG(T) concentrations do not reach adult levels until approximately 10 months of age,69 In colostrum-deprived foals, there is an earlier and more rapid increase in autogenous immunoglobulin synthesis, detectable as early as 2 weeks of age. 32 By 3 to 4 months of age, concentrations of immunoglobulin are similar in colostrum-fed and colostrum-deprived foals, Failure of Passive Transfer of Immunoglobulin
Septicemia is one of the major causes of neonatal foal morbidity and mortality worldwide B,15, 37 and a positive correlation between FPT and the incidence of equine neonatal septicemia has been demonstrated in several studies,3B, so, 52, 67 FPT has been defined variably as a serum IgG concentration at 24 hours of age of less than 200 mg/ dL, less than 400 mg/dL, and less than 800 mg/dL.3B, 54, 61 The incidence of FPT «400 mg/ dL) in foals has been estimated at 3% to 25%.2,13,35,50,54,60,64 Although this variation in incidence has been attributed largely to management practices, in one survey of 158 Standardbred mares on a single consistently managed farm, the incidence of FPT varied over a 5-year period from 4% to 14%, suggesting a possible effect of some factor or factors other than management. 14 There are three potential causes of FPT in foals: (1) ingestion of colostrum with low immunoglobulin concentration; (2) failure to ingest sufficient quantities of colostrum; and (3) failure to absorb colostral immunoglobulins from the gastrointestinal tract, Poor-quality colostrum with a low immunoglobulin concentration is a common cause of FPT in foals that are observed to nurse vigorously after birth,43,50 Colostral immunoglobulin concentration can vary widely between mares,54, 57, 73 Colostral immunoglobulin content can be measured or estimated by single radial immunodiffusion, refractometry, glutaraldehyde coagulation, or specific gravityY, 34, 42, 75 Measurement of specific gravity using a colostrometer is the most widely used method for estimating colostral immunoglobulin concentration in clinical practice. Good-quality colostrum is considered to have an IgG concentration greater than 3000 mg / dL, corresponding to a specific gravity of greater than 1.060,42 Insufficient IgG concentration in colostrum may result from prelactation, premature foaling, a genetic defect in the mare's ability to concentrate immunoglobulins into colostrum, or other factors.6l Prelactation, that is, lactation before parturition, is probably the most common cause of subnormal colostral immunoglobulin content, Mares at greatest risk for producing colostrum with low immunoglobulin content include mares older than
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15 years of age, those that foal early in the year, and Standardbred mares. 43 A failure to ingest sufficient quantities of colostrum within the first 6 to 12 hours of life is another common cause of FPT. Foals that are orphaned or rejected at birth, too weak to stand, or who are unable or lack the desire to suckle are unlikely to ingest sufficient colostrum and are at high risk for FPT. Malabsorption is often incriminated as the cause of FPT in foals that vigorously suckle adequate quantities of high quality colostrum. Glucocorticoids enhance maturation of small intestinal epithelial cells and loss of their specialized absorptive abilities 20, 22 leading to speculation that stress, with release of endogenous corticosteroids, may decrease immunoglobulin absorption in foals28, 61; however, administration of adrenocorticotrophic hormone to increase endogenous cortisol concentrations did not adversely affect absorption of immunoglobulin in experimental foals 1o and obvious stress factors are often not observed in foals with apparent impaired immunoglobulin absorption. 54 Several studies have examined epidemiologic risk factors for FPT in foalsY, 54, 64 In one study of 361 Standardbred mares in North America, the time of foaling (December to March) and a low foal examination score (a subjective measure of foal vigor, maturity, and general health) were the primary risk factors associated with FPTY An evaluation of 158 Standardbred mares foaling at least three times in a 5-year period revealed no significant relationship between having an FPT foal one year and having an FPT foal in subsequent years. 8 A subgroup of 10 mares, however, was identified that had multiple FPT foals; these mares accounted for almost half (48.2%) of FPT foals over the 5-year period 14 (DC Sellon, unpublished data, 1989). Colostral IgG content was not determined in these mares. In a separate study of 343 Thoroughbred foals in Australia, foals born late in the season (October to December) were at increased risk for FPT. The degree of assistance required at parturition and the presence of a peri parturient problem in the mare or foal were also significantly associated with FPT. 64
Diagnosis of Failure of Passive Transfer
Serum IgG concentrations in foals may be determined as early as 6 to 12 hours after ingestion of colostrum; however, routine determination of serum IgG concentrations in otherwise healthy foals is generally recommended at approximately 18 to 24 hours of age to ensure there has been adequate time for maximal immunoglobulin absorption. Most equine veterinarians currently recommend a minimum serum IgG concentration of 800 mg/ dL for optimal passive immunity. The most quantitatively accurate diagnostic test widely available to equine practitioners, either through diagnostic laboratories or a commercial kit, is the single radial immunodiffusion (SRID) test. This test, however, is relatively expensive as compared with other screening tests and requires a mini-
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mum of 24 hours for results, often making it impractical when rapid diagnosis and treatment of a critically-ill foal is desired. A wide variety of economical quick screening tests are available for diagnosis of FPT in foals. 1, 3-5, 12, 63, 70 Criteria for selecting a screening test for FPT include overall accuracy, time necessary to perform the test, ease of performance, and costP Total serum protein concentration may provide a quick and inexpensive estimate of immunoglobulin absorption but is not recommended for accurate assessments on a routine basis?O The zinc sulfate turbidity41 and glutaraldehyde coagulation tests 12 are inexpensive and can provide results in less than 1 hour, Nevertheless, many practitioners prefer the ease and convenience of enzyme immunoassay tests. 5, 12 Most screening tests are accurate at identification of foals with complete FPT, but there is some variability in the accuracy of their detection of marginally deficient foals P When in doubt, results should be confirmed with the SRID test Prevention and Treatment of Failure of Passive Transfer
Foals that are completely colostrum deprived (IgG < 200 mg/ dL) are at extremely high risk for sepsis even when management practices are optima1. 67 The majority of foals presenting for treatment of sepsis have concurrent FPT38, 50; however, partial FPT (IgG concentration of 200-800 mg/ dL) is not always associated with increased prevalence of illness or death,2, 13 This apparent discrepancy suggests that other management practices, in combination with even minimal ingestion of colostrum, may be important in preventing sepsis. Oral ingestion of any quantity of colostrum or milk may be associated with reduced illness in foals because of rapid gut closure and prevention of absorption of bacteria across the gut wal1. 47 Therefore, good hygiene during the periparturient period and prevention of exposure to pathogeniC bacteria during prolonged udder seeking or delayed feeding should decrease the incidence of septicemia even when total quantities of IgG absorbed from colostrum are comparatively low,47 If FPT is likely in a foal because of premature lactation, lack of colostral intake, or low-quality colostrum, an alternative colostral source can be administered orally or by nasogastric tube, preferably within a few hours of birth, The quantity of colostrum necessary depends on the IgG concentration of the colostrum, the size of the foal, and the efficiency of absorption of IgG from the gastrointestinal tract Foals fed approximately 1.5 g of colostral IgG/kg of body weight had acceptable serum IgG concentrations at 12 hours of life,43 The administration of a minimum of 1 to 2 liters of colostrum with a specific gravity of greater than 1.060 is recommended for a 45-kg foal. 44 Feedings should begin at 1 to 2 hours of age in volumes of 200 to 300 mL per feeding. If good-quality equine colostrum is not available, bovine colostrum25, 39, 40 or one of a variety of equine IgG supplements9, 45, 74 may
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be administered orally. Bovine immunoglobulin is absorbed by foals after ingestion of bovine colostrum but has a serum IgG half-life of only 7 to 10 days.25. 40 Although bovine colostrum was satisfactory for the raising of foals under experimental conditions, there was a fairly high incidence of respiratory disease, emphasizing the desirability of using equine colostrum whenever possible. 25 If used, a minimum of 1 to 2 liters of good-quality bovine colostrum should be administered orally in the first 12 hours of life. Lyophilized equine IgG is available commercially as a colostrum substitute. A total of 50 to 70 g of IgG is recommended to raise blood IgG levels above 400 mg/ dL in a foal that has been completely colostrum deprived. 74 Oral plasma or serum also may be administered to foals with FPT; however, relatively large volumes may be needed (2-4 L) to achieve adequate foal IgG concentration. The best treatment for FPT in foals is prevention, including provision of colostrum or colostrum substitutes to high-risk foals that are less than 12 hours old. In those foals with unacceptably low serum IgG concentration after 12 to 18 hours of life, however, intravenous plasma therapy is indicated. Foals with a serum IgG of less than 200 mg / dL at . 24 hours of age, regardless of their health or management status, should . be treated with intravenous plasma in sufficient quantity to increase IgG concentration to a minimum of 800 mg/ dL. Retrospective studies of FPT in foals suggest that an otherwise healthy foal with no other known risk factors for sepsis and an IgG concentration of 400 to 800 mg / dL may not require plasma transfusion to provide adequate immune protection in the first weeks of life. 2. 13 If plasma transfusions are not administered to these foals, however, owners should understand the risks and the foals should be closely monitored and maintained in an environment with minimal exposure to potential pathogens. High-risk foals (premature, dysmature, placentitis, weak, etc.) with IgG concentrations less than 800 mg/ dL at 18 to 24 hours should receive intravenous plasma transfusions. There are several excellent commercial sources of equine plasma. Commercial products are convenient and relatively safe because donors are screened for major alloantigen or alloantibody problems and infectious diseases and are vaccinated against common equine pathogens. Plasma IgG concentrations usually are specified. Alternatively, plasma can be obtained from donor horses housed in the same environment as the foal to be treated. This has the advantage of increasing the likelihood of providing optimal antibody concentrations against pathogens unique to the foal's local environment. The ideal plasma donor should not have any Aa and Qa erythrocyte alloantigen and alloantibody problems and have a minimum plasma IgG concentration of 1200 mg/ dL (12 gil). In the average 45-kg foal, 1 L of intravenous plasma with average immunoglobulin concentration provides the foal with approximately 12 g of IgG and increases the serum IgG concentration by 200 to 300 mg/ dL.37 Two to 4 L may be necessary to achieve a final serum IgG concentration of greater than 800 mg/ dL in a foal with complete FPT (initial IgG <200 mg/ dL) depending on the IgG concentration of donor
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plasma. If the concentration of IgG in donor plasma is known, the approximate volume required for transfusion can be estimated. A dose of 200 mg / kg of IgG in normal foals raised the serum IgG concentration by 450 mg / dL; a dose of 400 mg / kg of IgG in normal foals raised the serum IgG by 575 mgt dL.77 Septic foals may require a greater total volume of plasma to increase serum IgG concentrations by the same amount, and a total dose of 500 mg IgG/kg (approximately 40 mL/kg) has been recommended for these patients. 77 Ideally, serum IgG concentrations should be determined after administration of a plasma transfusion to confirm that the desired increase has been achieved. Immunoglobulin in transfused plasma is rapidly equilibrated into extravascular spaces, catabolized, or used in immune interactions. In normal foals receiving plasma transfusions at 1 day of age, a decrease of 30% in serum IgG concentration was observed by 7 days of age?6 This decrease may be even more profound in septic foals. Before administration, plasma should be thawed and warmed to body temperature. Previously frozen plasma should be used as soon as possible after thawing. All blood products administered intravenously should be administered through an in-line blood filter to remove fibrin strands. Even when donors have been typed and crossmatches are compatible, the initial transfusion flow rate should be slow to assess for unexpected adverse reactions. A rate of 0.1 mL/kg for 10 to 20 minutes is appropriate. This would be approximately 5 to 10 mL over 10 to 20 minutes for a 50-kg foal. During this time the recipient foal should be monitored for signs of adverse reactions. If there are no adverse reactions at this initial flow rate, the remainder of the transfusion may be administered at rates of up to 20 to 30 mL/kg/h. Slower flow rates are generally safer because transfusion reactions can be recognized before large volumes are administered. Slower infusion rates are recommended for foals with suspected or confirmed endotoxemia or septicemia. Rapid flow rates in normovolemic foals may induce iatrogenic volume overload. The foal's vital signs and behavior should be monitored throughout the transfusion and the flow rate slowed or stopped if significant changes are observed. LYMPHOSARCOMA-ASSOCIATED IMMUNODEFICIENCY
Several forms of immunodeficiency have been described in horses with lymphosarcoma. Acquired selective IgM deficiency is the most commonly described. 17, 19, 60 Affected horses may experience recurrent or persistent infections in addition to signs attributable to the underlying neoplasia. In one horse, neoplastic cells were identified as T-suppressor cells, suggesting a potential mechanism for the IgM deficiency.62 Diminished lymphocyte blastogenesis responses indicative of impaired T-cell function have been described in two horses with lymphosarcoma, one of which had concurrent IgM deficiencyP Both horses presented with
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signs of bacterial pneumonia as well as signs referable to the underlying neoplastic condition. These cases suggest that lymphosarcoma with secondary immunodeficiency should be suspected in adult horses with persistent infections that are refractory to treatment. OTHER ACQUIRED IMMUNODEFICIENCIES
There have been several reports of adult horses with presumed secondary or acquired immunodeficiencies of undetermined origin. A 7year-old Appaloosa gelding with Rhodococcus equi bacteremia and pneumonia had an absolute lymphopenia and abnormal lymphocyte blastogenesis responses consistent with impaired T-cell function. I S This gelding also had decreased serum immunoglobulin concentrations and a lack of humoral responses to vaccination consistent with impaired B-cell function. At necropsy, lymphoid tissue was depleted. Is A 3-year-old Quarter Horse with pneumonia and chronic diarrhea had IgM deficiency secondary to decreased B-cell numbers. Other immunoglobulin isotypes were also decreased, as was T-cell function. No evidence of lymphosarcom,a was found at necropsy.46 DRUG-INDUCED IMMUNE SUPPRESSION
Secondary immunosuppression can occur as a result of administration of a drug that suppresses some aspect of the immune system, most commonly by killing or inhibiting the function of lymphocytes. Sometimes these are drugs that are being purposefully administered to suppress undesirable immune-mediated phenomena (e.g., corticosteroids for treatment of immune-mediated hemolytic anemia); at other times, these are adverse drug reactions encountered while treating other illnesses (e.g., chemotherapy for treatment of neoplastic disease processes). Corticosteroids are the most frequently incriminated therapeutic agent in causing drug-induced immune suppression. In horses, corticosteroids may be used for the treatment of a variety of ailments including immune-mediated diseases, chronic obstructive pulmonary and reactive airway diseases, myositis, neurologic disorders, and shock states. Immunosuppressive doses of corticosteroids can exacerbate pre-existing infectious diseases 36 or decrease resistance to environmental pathogens. 48 Corticosteroids are potent anti-inflammatory agents whose effects are mediated through binding to intracytoplasmic steroid receptors. Steroid-receptor complexes are transported to the nucleus where they bind cellular DNA regulatory sequences and alter gene expression to enhance or inhibit specific protein production. The exact mechanisms by which corticosteroids inhibit immune function are unclear. Corticosteroids induce a lymphopenia by either lymphocyte lysis (mouse, rat, rabbit) or redistribution of circulating lymphocytes to lymphoid organs
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such as lymph nodes, bone marrow, and spleen (humans and most domestic animals).16 They are suppressive to macrophage phagocytic function, impair the killing of ingested organisms, impair secretion of monokines, and inhibit antigen processing and presentation. 16, 71 Cellmediated immunity is impaired through a variety of mechanisms including T-cell lymphopenia, suppression of proliferation in response to mitogen stimulation, altered patterns of cytokine production, and decreased antigen presentation. Humoral immunity is impaired indirectly through alterations in T-cell responses, enhanced catabolism of immunoglobulins, and decreased antigen presentation. 16 A variety of chemotherapeutic agents and other drugs that are widely used in humans and small animals have the potential to markedly suppress immune function with resultant secondary infections; however, these drugs are not used frequently in horses. Chemotherapeutic agents for the treatment of neoplasia are often cytotoxic to mature and developing lymphocytes, neutrophils, and mononuclear phagocytes, and therapy with these agents almost always is associated with a period of immunosuppression. MISCELLANEOUS CAUSES OF IMMUNE SUPPRESSION
Many viral infections transiently suppress local or systemic immune responses or both,56 predisposing to secondary infections. Chronic fungal or parasitic infections also may lead to immune suppression. Severe septicemia or endotoxemia may impair cell-mediated immune responses and decrease neutrophil numbers and bactericidal function. Patients with advanced neoplastic disease are susceptible to infections because of impaired cell-mediated and humoral immune responses. This may be the result of an abnormal bone marrow environment negatively affecting lymphocyte maturation, abnormal patterns of cytokine production and release, or impaired proliferative response caused by anergy. Severe bone marrow infiltrative disease impairs immune function by decreasing the numbers of neutrophils and having adverse effects on lymphocyte maturation processes. Protein-calorie malnutrition similarly is associated with impaired immune function and increased susceptibility to infection. Other metabolic disturbances, including a variety of vitamin and/ or mineral deficiencies also may adversely affect immune function. Exercise stress may transiently impair neutrophil antimicrobial functions, predisposing to infection. 78 Other forms of stress such as prolonged transport also may have negative effects on immune function. SUMMARY
FPT of immunoglobulin in foals is the commonest form of acquired immunodeficiency in horses. FPT predisposes foals to bacterial ihfections
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and septicemia and easily is preventable and treatable if breeding farms and veterinarians are attentive to optimum foaling management practices. Other forms of acquired immunodeficiencies are uncommon in horses, although immune function may be transiently suppressed by a wide variety of drugs, infections, or other conditions. As immunologic testing becomes more sophisticated and more readily available to equine practitioners, acquired immunodeficiencies are likely to be characterized more frequently in horses. References 1. Baird AN, Pugh DG, Rupp GP, et al: Detection of immunoglobulin G in the neonate. Equine Vet Sci 7:124-129, 1987 2. Baldwin JL, Cooper WL, Vanderwall DK, et al: Prevalence (treatment days) and severity of illness in hypogammaglobulinemic and normogammaglobulinemic foals. J Am Vet Med Assoc 198:423--428, 1991 3. Bauer IE, Brooks TP: Immunoturbidimetric quantification of serum immunoglobulin G concentration in foals. Am J Vet Res 51:1211-1214, 1990 4. Beetson SA, Hilbert BJ, Mills IN: The use of the glutaraldehyde coagulation test of· detection of hypogammaglobulinaemia in neonatal foals . Aust Vet J 62:279-281, 1985 ' 5. Bertone H, Jones RL, Curtis CR: Evaluation of a kit for determination of serum immunoglobulin G concentration in foals. J Vet Intern Med 2:181-183, 1988 6. Besser TE, Gay Ce, McGuire Te, et al: Passive immunity to bovine rotavirus infection associated with transfer of serum antibody into the intestinal lumen. J Virol 62:22382242,1988 7. Besser TE, McGuire TC, Gay CC, et al: Transfer of functional immunoglobulin G (IgG) antibody into the gastrointestinal tract accounts for IgG clearance in calves. J Virol 62:2234-2237, 1988 8. Brewer BD, Koterba AM: Bacterial isolates and susceptibility patterns in foals in a neonatal intensive care unit. Compendium on Continuing Education for the Practicing Veterinarian 12:1773-1781, 1990 9. Burton Se, Hintz HF, Kernen MJ, et al: Lyophilized hyperimmune equine serum as a source of antibodies for neonatal foals. Am J Vet Res 42:308-310, 1981 10. Carrick JB, Pollitt Ce, Thompson HL, et al: Failure of the administration of ACTH to affect the absorption of colostral immunoglobulin in neonatal foals. Equine Vet J 19:545--547, 1987 11. Cash RSG: Colostral quality determined by refractometry. Equine Veterinary Education 11:36-38, 1999 12. Clabough DL, Conboy HS, Roberts MC: Comparison of four screening techniques for the diagnosis of equine neonatal hypogammaglobulinemia. J Am Vet Med Assoc 194:1717-1720, 1989 13. Clabough DL, Levine JF, Grant GL, et al: Factors associated with failure of passive transfer of colostral antibodies in Standardbred foals. J Vet Intern Med 5:335-340, 1991 14. Clabough DL: Factors associated with failure of passive transfer in Standardbred foals. Proceedings of the American College of Veterinary Internal Medicine 8:555--558, 1990 15. Cohen ND: Causes of and farm management factors associated with disease and death in foals. J Am Vet Med Assoc 204:1644-1651, 1994 16. Cohn LA: The influence of corticosteroids on host defense mechanisms. J Vet Intern Med 5:95--104, 1991 17. Dopson Le, Reed SM, Roth JA, et al: Immunosuppression associated with lymphosarcoma in two horses. J Am Vet Med Assoc 183:1239-1241, 1983 18. Freestone JF, Hietala S, Moulton J, et al: Acquired immunodeficiency in a seven-yearold horse. J Am Vet Med Assoc 190:689-691, 1987 19. Furr M, Crisman M, Robertson J: Immunodeficiency associated with lymphosarcoma in a horse. J Am Vet Med Assoc 201:307-309, 1992
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20. Gillette DD, Filkins M: Factors affecting antibody transfer in the newborn puppy. Am J Physiol 210:419--422, 1966 21. Grosvenor CE, Picciano MF, Baumrucker CR: Hormones and growth factors in milk. Endocr Rev 14:710-728, 1993 22. Halliday R: Failure of some Hill lambs to absorb maternal gammaglobulin. Nature 205:614, 1965 23. Higgins WP, Gillespie JH, Robson DS: Studies of maternally-acquired antibodies in the foal to equine influenza Al and Au and equine rhinopneumonitis. Equine Veterinary Science 7:207-210, 1987 24. Hodgin Ee, McGuire Te, Perryman LE: Evaluation of delayed hypersensitivity responses in normal horses and immunodeficient foals. Am J Vet Res 39:1161-1167, 1978 25. Holmes MA, Lunn DP: A study of bovine and equine immunoglobulin levels in pony foals fed bovine colostrum. Equine Vet J 23:116-118, 1991 26. Ingram DG, Smith AN: Immunological responses of young animals: 1. Review of the literature. Can Vet J 6:194-204, 1965 27. Jan CL: Cellular components of mammary secretions and neonatal immunity: A review. Vet Res 27:403--416, 1996 28. Jeffcott LB: Passive immunity and its transfer with special reference to the horse. Bioi Rev 47:439--464, 1972 29. Jeffcott LB, Jeffcott TJ: Studies on passive immunity in the foal: 3. The characterisation and significance of neonatal proteinuria. Journal of Comparative Pathology 84:455, 1974c 30. Jeffcott LB: Duration of permeability of the intestine to macromolecules in the newlyborn foal. Vet Rec 88:340-341, 1971 31. Jeffcott LB: Studies on passive immunity in the foal: 2. The absorption of 125I-Iabelled PVP (polyvinyl pyrrolidone) by the neonatal intestine. Journal of Comparative Pathology 84:279-289, 1974b 32. Jeffcott LB: Studies on passive immunity in the foal: 1. Gammaglobulin and antibody variations associated with the maternal transfer of immunity and the onset of active immunity. Journal of Comparative Pathology 84:93-101, 1974 33. Jeffcott LB: The transfer of passive immunity to the foal and its relation to immune status after birth. J Reprod Fertil Suppl 23:727-733, 1975 34. Jones D, Brook D: Investigation of the Gamma-Check-C test as a means of evaluating IgG levels in equine colostrum. Equine Veterinary Science 15:269-271, 1995 35. Kohn CW, Knight D, Hueston W, et al: Colostral and serum IgG, IgA, and IgM concentrations in Standardbred mares and their foals at parturition. J Am Vet Med Assoc 195:64-68, 1989 36. Kono Y, Hirasawa K, Fukunaga Y, et al: Recrudescence of equine infectious anemia by treatment with immunosuppressive drugs. National Institute of Animal Health Quarterly (Tokyo) 16:8-15, 1976 37. Koterba AM, Brewer B, Drummond WH: Prevention and control of infection. Vet Clin North Am Equine Pract 1:41-50, 1985 38. Koterba AM, Brewer BD, Tarplee FA: Clinical and clinicopathological characteristics of the septicemic neonatal foal: Review of 38 cases. Equine Vet J 16:376-382, 1984 39. Lavoie JP, Spensley MS, Smith BP, et al: Complement activity and selected hematologic variables in newborn foals fed bovine colostrum. Am J Vet Res 50:1532-1536, 1989a 40. Lavoie JP, Spensley MS, Smith BP, et al: Absorption of bovine colostral immunoglobulins G and M in newborn foals. Am J Vet Res 50:1598-1603, 1989b 41. LeBlanc MM, Hurtgen JP, Lyle S: A modified zinc sulfate turbidity test for the detection of immune status in newly born foals. Equine Veterinary Science 10:36--40, 1990 42. LeBlanc MM, McLaurin BI, Boswell R: Relationships among serum immunoglobulin concentration in foals, colostral specific gravity, and colostral immunoglobulin concentration. J Am Vet Med Assoc 189:57-60, 1986 43. LeBlanc MM, Tran T, Baldwin JL, et al: Factors that influence passive transfer of immunoglobulins in foals. J Am Vet Med Assoc 200:179-183, 1992 44. LeBlanc MM: Immunologic considerations. In Koterba AM, Drummond WH, Kosch PC (eds): Equine Clinical Neonatology. Philadelphia, Lea & Febiger, 1990, pp 275-294 45. Liu IKM, Brown e, Myers RC, et al: Evaluation of intravenous administration of
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46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.
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concentrated immunoglobulin G to colostrum-deprived foals. Am J Vet Res 52:709712, 1991 MacLeay JM, Ames TR, Hayden OW, et al: Acquired B lymphocyte deficiency and chronic enterocolitis in a 3-year-old Quarter Horse. Vet Immunol Immunopathol 57:4957, 1997 Madigan JE: Method for preventing neonatal septicemia, the leading cause of death in the neonatal foal. Proc Am Assoc Equine Pract 43:17-19, 1997 Mair TS: Bacterial pneumonia associated with corticosteroid therapy in three horses. Vet Rec 138:205-207, 1996 Martin BR, Larson KA: Immune response of equine fetus to coliphage T2 . Am J Vet Res 34:1363-1364, 1973 McGuire TC, Crawford TB, Hallowell AL, et al: Failure of colostral immunoglobulin transfer as an explanation for most infections and neonatal deaths in foals. J Am Vet Med Assoc 170:1302-1304, 1977 McGuire TC, Crawford TB: Passive immunity in the foal: Measurement of immunoglobulin classes and specific antibody. Am J Vet Res 34:1299-1303, 1973 McGuire TC, Poppie MJ, Banks KL: Hypogammaglobulinemia predisposing to infection in foals. J Am Vet Med Assoc 166:71-75, 1975 Morgan DO, Bryans JT, Mock RE: Immunoglobulins produced by the antigenized equine fetus. J Reprod Fertil Suppl 23:735-738, 1975 Morris DO, Meirs DA, Merryman GS: Passive transfer failure in horses: Incidence and causative factors on a breeding farm. Am J Vet Res 46:2294-2299, 1985 , Nathanielsz PW, Comline RS, Silver M, et al: Cortisol metabolism in the fetal and , neonatal sheep. J Reprod Fertil Suppl 16:39-59, 1972 Olsen RG: Immune dysfunctions associated with viral infections. Compendium on Continuing Education for the Practicing Veterinarian 6:422-427, 1984 Pearson RC, Hallowell AL, Bayly WM, et al: Times of appearance and disappearance of colostral IgG in the mare. Am J Vet Res 45:186--190, 1984 Perryman LE, Buening GM, McGuire TC, et al: Fetal tissue transplantation for immunotherapy of combined immunodeficiency in horses. Clin Immunol Immunopathol 12:238-251, 1979 Perryman LE, McGuire TC, Torbeck RL: Ontogeny of lymphocyte function in the equine fetus. Am J Vet Res 41:1197-1200, 1980 Perryman LE, McGuire TC: Evaluation for immune system failure in horses and ponies. J Am Vet Med Assoc 76:1374-1377, 1980a Perryman LE: Immunological management of young foals. Compendium on Continuing Education for the Practicing Veterinarian 3(suppl):223-228, 1981 Perryman LE, Wyatt CR, Magnuson NS: Biochemical and functional characterization of lymphocytes from a horse with lymphosarcoma and igM deficiency. Comp Immunol Microbiol Infect Dis 7:53-62, 1984 Pugh DG, White SL: Commercially available tests for identification of the colostrumdeficient foal. Equine Practice 9:8-11, 1987 Raidal SL: The incidence and consequences of failure of passive transfer of immunity on a Thoroughbred breeding farm. Aust Vet J 73:201-206, 1996 Reilly WJ, Macdougall OF: The metabolism of IgG in the newborn foal. Res Vet Sci 14:136--137, 1973 Rejnek J, Prokesova L, Sterzl J, et al: The presence of IgG and IgM in full term horse umbilical cord sera. Immunochemistry 10:397-399, 1973 Robinson JA, Allen GK, Green EM, et al: A prospective study of septicaemia in colostrum-deprived foals. Equine Vet J 25:214-219, 1993 Rouse BT, Ingram DG: The total protein and immunoglobulin profile of equine colostrum and milk. Immunology 19:901-907, 1970 Rouse BT: The immunoglobulins of adult equine and foal sera: A quantitative study. Br Vet J 127:45-52, 1971 Rumbaugh GE, Ardans AA, Ginno 0, et al: Measurement of neonatal equine immunoglobulins for assessment of colostral immunoglobulin transfer: Comparison of single radial immunodiffusion with the zinc sulfate turbidity test, serum electrophoresis,
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refractometry for total serum protein, and the sodium sulfite precipitation test. J Am Vet Med Assoc 172:321-325, 1978 Schaffner A, Schaffner T: Glucocorticoid-induced impairment of macrophage antimicrobial activity: Mechanisms and dependence on the state of activation. Reviews of Infectious Diseases 9(suppl):620-629, 1987 Tizard I: In Veterinary Immunology, An Introduction, ed 3. Philadelphia, WE Saunders, 1987, p 171 Townsend HGG, Tabel H, Bristol FM: Induction of parturition in mares: Effect on passive transfer of immunity to foals. J Am Vet Med Assoc 182:255-257, 1983 Vivrette SL, Young K Manning S, et al: Efficacy of seramune in the treatment of failure of passive transfer in foals. Proceedings of the American Association of Equine Practitioners 44:136-137, 1998 Waelchli RO, Hassig M, Eggenberger E, et al: Relationships of total protein, specific gravity, viscosity, refractive index and latex agglutination to immunoglobulin G concentration in mare colostrum. Equine Vet J 22:39-42, 1990 White S: Exogenous IgG in the treatment of foals with failure of passive transfer and / or sepsis. Proceedings of the American College of Veterinary Internal Medicine 6:145-147, 1988 White S: The use of plasma in foals with failure of passive transfer and / or sepsis. Proceedings of the American Association of Equine Practitioners 35:215-218, 1989 Wong CW, Smith SE, Thong YH, et al: Effects of exercise stress on various immune functions in horses. Am J Vet Res 53:1414-1417, 1992 XU RJ: Development of the newborn GI tract and its relation to colostrum/milk intake: A review. Reprod Fertil Dev 8:35-48, 1996 Zou S, Brady HA, Hurley WL: Protective factors in mammary gland secretions during the periparturient period in the mare. J Equine Veterinary Science 18:184-188, 1998
Address reprint requests to Debra C. Sellon, DVM, PhD Department of Veterinary Clinical Sciences College of Veterinary Medicine Washington State University Pullman, WA 99164 e-mail: [email protected]
0749--D739 / 00 $15.00
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SECONDARY IMMUNODEFICIENCIES OF HORSES Debra C. Sellon, DVM, PhD
Immunodeficiencies are disorders resulting from the absence ' or failure of function of one or more components of the immune system. Secondary or acquired immunodeficiencies occur as a consequence of extrinsic or environmental conditions. The commonest secondary immunodeficiency of horses is failure of passive transfer of immunoglobulin in neonatal foals. Other causes include immunodeficiency or immunosuppression secondary to an underlying disease process (e.g., infection, malnutrition, neoplasia), irradiation, or drug therapy (e.g., corticosteroids). Regardless of cause, immunodeficiency disorders are characterized by an increased susceptibility to infection. Foals with failure of passive transfer are at increased risk for septicemia or other bacterial infections. Adult horses with acquired immunodeficiencies often present with clinical signs of recurrent or persistent infections, poor response to appropriate antimicrobial therapy, or infection with normally nonpathogenic organisms. In generat defects in humoral immunity predispose to infection with pyogenic bacteria, whereas deficiencies in cell-mediated immunity predispose to overwhelming infection by organisms that are generally considered nonpathogenic in immune-competent animals (e.g., Candida albicans, Cryptosporidium spp., adenovirus). Often the acquired immunodeficiencies affect both humoral and cell-mediated immunity.
From the Department of Veterina~y C'linical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington
VETERINARY CLINICS OF NORTH AMERICA: EQUINE PRACTICE VOLUME 16 • NUMBER 1 • APRIL 2000
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FAILURE OF PASSIVE TRANSFER OF IMMUNOGLOBULINS
Lymphocytes capable of responding to antigenic stimulation are demonstrable in equine fetal tissues as early as day 80 to 100 of gestation, 58, 59 and injected antigens can elicit a humoral response (demonstrable serum IgM and IgG) by day 200 of gestation,49,53 Therefore, foals are essentially immune competent at birth with detectable, but low, quantities of serum immunoglobulin, primarily IgM,66,69 Exposure to pathogenic organisms at birth stimulates a primary immune response, but it takes 10 to 14 days for that response to become protective. 51 ,61 The rate and magnitude of antibody synthesis in response to specific antigenic stimulation in foals has not been compared with that of adult horses 26 but may be diminished because of immature cell-mediated functions at birth.24 During the lag time between exposure to infectious agents and development of a protective immune response, foals can easily be overwhelmed by infectious agents. Passive immunity, acquired from the dam, is essential for protection during the first month of life. Maternal immunoglobulins are not transferred transplacentally in horses because of a diffuse epitheliochorial placenta, which is impermeable to macromolecules, thus preventing the fetus from receiving antibodies or antigens present in maternal circulation. The result is an equine neonate that is born profoundly hypogammaglobulinemic. In the interim between birth and production of adequate spectrum and quantity of specific immunoglobulin by the foal, passive immunity is dependent on ingestion of colostrum. This specialized milk is produced during the last 2 to 4 weeks of gestation as the mammary gland concentrates immunoglobulin from the blood into mammary secretions. 28, 32, 51 Failure of the foal to ingest or absorb sufficient immunoglobulin from colostrum is referred to as failure of passive transfer of immunoglobulin (FPT). FPT is the most important risk factor for localized or systemic bacterial infections in foals during the first month of life and is the commonest immunologic disorder of foals. 38, 50
Production and Absorption of Colostrum
Colostrum is produced in the last few weeks of pregnancy under the influence of estrogens and progesterone and contains components from the mare's blood as well as locally (mammary gland) produced substances. Soluble substances including immunoglobulin,57 cytokines,27 growth factors,21 hormones,21 and enzymes such as lysozyme80 have a positive influence on neonatal immunity and gastrointestinal maturation?9 Cellular components of colostrum include lymphocytes, macrophages, neutrophils, and epithelial cells and are likely to be important in development of local gastrointestinal immunity and modulation of responses to antigens in the newborn,27 Maternal cells in colostrum cross
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the intestinal barrier and are detectable in intestinal mucosa, mesenteric lymph nodes, blood, lungs, liver, and spleen of the neonate. Although colostrum contains a wide variety of soluble and cellular components that are likely to affect immune function in neonates, at this time only colostral immunoglobulins have been linked specifically to passive immunity and susceptibility to infection in the foal.3 8, 50 The predominant immunoglobulin in equine colostrum is IgG (1500-5000 mg/dL) with lesser quantities of IgA (500-1500 mg/dL), IgM (100-350 mg/ dL), and IgG(T) (500-2500 mg/ dL).72 Colostral IgG concentration may exceed 9000 mg/ dL in some mares. 57 Immunoglobulin is preferentially concentrated from blood into the mammary gland secretions beginning 2 to 3 weeks before parturition. 32 Protein concentrations in colostrum decline precipitously in the first 8 hours after parturition as the foal suckles, and immunoglobulin concentrations become negligible within 12 hours when mares are actively suckled. 32, 57, 68 Rate of disappearance of colostral IgG, however, may be influenced by other factors including breed, initial colostral IgG concentrations, or both. 57 IgA is the predominant immunoglobulin in equine milk. Normal foals suckle colostrum within 1 to 3 hours of birth, ~nd maternal antibodies are detectable in the foal's serum within 6 hours. Colostral proteins are absorbed by specialized cells distributed throughout the small intestine. 33 Absorption of large macromolecules is nonselective and occurs by pinocytosis. Absorbed proteins are discharged into the intercellular space, passing into lacteals, and then the systemic circulation. Macromolecular absorption is maximal soon after birth and decreases rapidly with approximately 22% efficiency at 3 hours after birth, decreasing linearly to less than 1% by 20 hours. 3o,31 The cessation of absorption of macromolecules within 24 hours after birth results from a rapid turnover of absorptive cells, possibly triggered by high levels of adrenal corticosteroids at the time of parturition. 33, 55 Foals that receive colostrum within a few hours of birth experience transient proteinuria with urinary protein concentrations peaking by 6 to 12 hours and declining between 24 and 36 hours.29 This urinary protein consists of low molecular weight milk proteins, and the cessation of proteinuria may be a reflection of cessation of macromolecular absorption. 33 Passive antibody concentrations in foals decline rapidly during the first 4 weeks of life, largely because of catabolism of antibody and dilution in the increasing plasma volume of the growing foal.3 3 Transfer of functional IgG into the gastrointestinal tract also may account for partial clearance from the blood and enhanced gastrointestinal immunity.6, 7 The half-life for disappearance of maternal IgG in foals is approximately 20 to 30 days.23. 32, 65 Most maternal immunoglobulins are minimally detectable by 6 months of age, although this depends on the initial concentration of immunoglobulin absorbed. Antibodies to specific infectious agents may persist longer depending on the original colostral concentration and sensitivity of the detection method used. 33 As passive antibody concentrations wane in the foal, autogenous
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immunoglobulin synthesis (active immunity) increases. The result in colostrum-fed foals is a nadir in total serum IgG concentration at approximately 1 to 3 months of age followed by gradually increasing concentrations to adult levels. 61,69 In colostrum-fed foals autogenous IgG is first detectable in serum at approximately 4 weeks of age,32 IgM concentrations reach adult levels at approximately 3 to 5 months of age, whereas IgG and IgG(T) concentrations do not reach adult levels until approximately 10 months of age,69 In colostrum-deprived foals, there is an earlier and more rapid increase in autogenous immunoglobulin synthesis, detectable as early as 2 weeks of age. 32 By 3 to 4 months of age, concentrations of immunoglobulin are similar in colostrum-fed and colostrum-deprived foals, Failure of Passive Transfer of Immunoglobulin
Septicemia is one of the major causes of neonatal foal morbidity and mortality worldwide B,15, 37 and a positive correlation between FPT and the incidence of equine neonatal septicemia has been demonstrated in several studies,3B, so, 52, 67 FPT has been defined variably as a serum IgG concentration at 24 hours of age of less than 200 mg/ dL, less than 400 mg/dL, and less than 800 mg/dL.3B, 54, 61 The incidence of FPT «400 mg/ dL) in foals has been estimated at 3% to 25%.2,13,35,50,54,60,64 Although this variation in incidence has been attributed largely to management practices, in one survey of 158 Standardbred mares on a single consistently managed farm, the incidence of FPT varied over a 5-year period from 4% to 14%, suggesting a possible effect of some factor or factors other than management. 14 There are three potential causes of FPT in foals: (1) ingestion of colostrum with low immunoglobulin concentration; (2) failure to ingest sufficient quantities of colostrum; and (3) failure to absorb colostral immunoglobulins from the gastrointestinal tract, Poor-quality colostrum with a low immunoglobulin concentration is a common cause of FPT in foals that are observed to nurse vigorously after birth,43,50 Colostral immunoglobulin concentration can vary widely between mares,54, 57, 73 Colostral immunoglobulin content can be measured or estimated by single radial immunodiffusion, refractometry, glutaraldehyde coagulation, or specific gravityY, 34, 42, 75 Measurement of specific gravity using a colostrometer is the most widely used method for estimating colostral immunoglobulin concentration in clinical practice. Good-quality colostrum is considered to have an IgG concentration greater than 3000 mg / dL, corresponding to a specific gravity of greater than 1.060,42 Insufficient IgG concentration in colostrum may result from prelactation, premature foaling, a genetic defect in the mare's ability to concentrate immunoglobulins into colostrum, or other factors.6l Prelactation, that is, lactation before parturition, is probably the most common cause of subnormal colostral immunoglobulin content, Mares at greatest risk for producing colostrum with low immunoglobulin content include mares older than
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15 years of age, those that foal early in the year, and Standardbred mares. 43 A failure to ingest sufficient quantities of colostrum within the first 6 to 12 hours of life is another common cause of FPT. Foals that are orphaned or rejected at birth, too weak to stand, or who are unable or lack the desire to suckle are unlikely to ingest sufficient colostrum and are at high risk for FPT. Malabsorption is often incriminated as the cause of FPT in foals that vigorously suckle adequate quantities of high quality colostrum. Glucocorticoids enhance maturation of small intestinal epithelial cells and loss of their specialized absorptive abilities 20, 22 leading to speculation that stress, with release of endogenous corticosteroids, may decrease immunoglobulin absorption in foals28, 61; however, administration of adrenocorticotrophic hormone to increase endogenous cortisol concentrations did not adversely affect absorption of immunoglobulin in experimental foals 1o and obvious stress factors are often not observed in foals with apparent impaired immunoglobulin absorption. 54 Several studies have examined epidemiologic risk factors for FPT in foalsY, 54, 64 In one study of 361 Standardbred mares in North America, the time of foaling (December to March) and a low foal examination score (a subjective measure of foal vigor, maturity, and general health) were the primary risk factors associated with FPTY An evaluation of 158 Standardbred mares foaling at least three times in a 5-year period revealed no significant relationship between having an FPT foal one year and having an FPT foal in subsequent years. 8 A subgroup of 10 mares, however, was identified that had multiple FPT foals; these mares accounted for almost half (48.2%) of FPT foals over the 5-year period 14 (DC Sellon, unpublished data, 1989). Colostral IgG content was not determined in these mares. In a separate study of 343 Thoroughbred foals in Australia, foals born late in the season (October to December) were at increased risk for FPT. The degree of assistance required at parturition and the presence of a peri parturient problem in the mare or foal were also significantly associated with FPT. 64
Diagnosis of Failure of Passive Transfer
Serum IgG concentrations in foals may be determined as early as 6 to 12 hours after ingestion of colostrum; however, routine determination of serum IgG concentrations in otherwise healthy foals is generally recommended at approximately 18 to 24 hours of age to ensure there has been adequate time for maximal immunoglobulin absorption. Most equine veterinarians currently recommend a minimum serum IgG concentration of 800 mg/ dL for optimal passive immunity. The most quantitatively accurate diagnostic test widely available to equine practitioners, either through diagnostic laboratories or a commercial kit, is the single radial immunodiffusion (SRID) test. This test, however, is relatively expensive as compared with other screening tests and requires a mini-
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mum of 24 hours for results, often making it impractical when rapid diagnosis and treatment of a critically-ill foal is desired. A wide variety of economical quick screening tests are available for diagnosis of FPT in foals. 1, 3-5, 12, 63, 70 Criteria for selecting a screening test for FPT include overall accuracy, time necessary to perform the test, ease of performance, and costP Total serum protein concentration may provide a quick and inexpensive estimate of immunoglobulin absorption but is not recommended for accurate assessments on a routine basis?O The zinc sulfate turbidity41 and glutaraldehyde coagulation tests 12 are inexpensive and can provide results in less than 1 hour, Nevertheless, many practitioners prefer the ease and convenience of enzyme immunoassay tests. 5, 12 Most screening tests are accurate at identification of foals with complete FPT, but there is some variability in the accuracy of their detection of marginally deficient foals P When in doubt, results should be confirmed with the SRID test Prevention and Treatment of Failure of Passive Transfer
Foals that are completely colostrum deprived (IgG < 200 mg/ dL) are at extremely high risk for sepsis even when management practices are optima1. 67 The majority of foals presenting for treatment of sepsis have concurrent FPT38, 50; however, partial FPT (IgG concentration of 200-800 mg/ dL) is not always associated with increased prevalence of illness or death,2, 13 This apparent discrepancy suggests that other management practices, in combination with even minimal ingestion of colostrum, may be important in preventing sepsis. Oral ingestion of any quantity of colostrum or milk may be associated with reduced illness in foals because of rapid gut closure and prevention of absorption of bacteria across the gut wal1. 47 Therefore, good hygiene during the periparturient period and prevention of exposure to pathogeniC bacteria during prolonged udder seeking or delayed feeding should decrease the incidence of septicemia even when total quantities of IgG absorbed from colostrum are comparatively low,47 If FPT is likely in a foal because of premature lactation, lack of colostral intake, or low-quality colostrum, an alternative colostral source can be administered orally or by nasogastric tube, preferably within a few hours of birth, The quantity of colostrum necessary depends on the IgG concentration of the colostrum, the size of the foal, and the efficiency of absorption of IgG from the gastrointestinal tract Foals fed approximately 1.5 g of colostral IgG/kg of body weight had acceptable serum IgG concentrations at 12 hours of life,43 The administration of a minimum of 1 to 2 liters of colostrum with a specific gravity of greater than 1.060 is recommended for a 45-kg foal. 44 Feedings should begin at 1 to 2 hours of age in volumes of 200 to 300 mL per feeding. If good-quality equine colostrum is not available, bovine colostrum25, 39, 40 or one of a variety of equine IgG supplements9, 45, 74 may
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be administered orally. Bovine immunoglobulin is absorbed by foals after ingestion of bovine colostrum but has a serum IgG half-life of only 7 to 10 days.25. 40 Although bovine colostrum was satisfactory for the raising of foals under experimental conditions, there was a fairly high incidence of respiratory disease, emphasizing the desirability of using equine colostrum whenever possible. 25 If used, a minimum of 1 to 2 liters of good-quality bovine colostrum should be administered orally in the first 12 hours of life. Lyophilized equine IgG is available commercially as a colostrum substitute. A total of 50 to 70 g of IgG is recommended to raise blood IgG levels above 400 mg/ dL in a foal that has been completely colostrum deprived. 74 Oral plasma or serum also may be administered to foals with FPT; however, relatively large volumes may be needed (2-4 L) to achieve adequate foal IgG concentration. The best treatment for FPT in foals is prevention, including provision of colostrum or colostrum substitutes to high-risk foals that are less than 12 hours old. In those foals with unacceptably low serum IgG concentration after 12 to 18 hours of life, however, intravenous plasma therapy is indicated. Foals with a serum IgG of less than 200 mg / dL at . 24 hours of age, regardless of their health or management status, should . be treated with intravenous plasma in sufficient quantity to increase IgG concentration to a minimum of 800 mg/ dL. Retrospective studies of FPT in foals suggest that an otherwise healthy foal with no other known risk factors for sepsis and an IgG concentration of 400 to 800 mg / dL may not require plasma transfusion to provide adequate immune protection in the first weeks of life. 2. 13 If plasma transfusions are not administered to these foals, however, owners should understand the risks and the foals should be closely monitored and maintained in an environment with minimal exposure to potential pathogens. High-risk foals (premature, dysmature, placentitis, weak, etc.) with IgG concentrations less than 800 mg/ dL at 18 to 24 hours should receive intravenous plasma transfusions. There are several excellent commercial sources of equine plasma. Commercial products are convenient and relatively safe because donors are screened for major alloantigen or alloantibody problems and infectious diseases and are vaccinated against common equine pathogens. Plasma IgG concentrations usually are specified. Alternatively, plasma can be obtained from donor horses housed in the same environment as the foal to be treated. This has the advantage of increasing the likelihood of providing optimal antibody concentrations against pathogens unique to the foal's local environment. The ideal plasma donor should not have any Aa and Qa erythrocyte alloantigen and alloantibody problems and have a minimum plasma IgG concentration of 1200 mg/ dL (12 gil). In the average 45-kg foal, 1 L of intravenous plasma with average immunoglobulin concentration provides the foal with approximately 12 g of IgG and increases the serum IgG concentration by 200 to 300 mg/ dL.37 Two to 4 L may be necessary to achieve a final serum IgG concentration of greater than 800 mg/ dL in a foal with complete FPT (initial IgG <200 mg/ dL) depending on the IgG concentration of donor
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plasma. If the concentration of IgG in donor plasma is known, the approximate volume required for transfusion can be estimated. A dose of 200 mg / kg of IgG in normal foals raised the serum IgG concentration by 450 mg / dL; a dose of 400 mg / kg of IgG in normal foals raised the serum IgG by 575 mgt dL.77 Septic foals may require a greater total volume of plasma to increase serum IgG concentrations by the same amount, and a total dose of 500 mg IgG/kg (approximately 40 mL/kg) has been recommended for these patients. 77 Ideally, serum IgG concentrations should be determined after administration of a plasma transfusion to confirm that the desired increase has been achieved. Immunoglobulin in transfused plasma is rapidly equilibrated into extravascular spaces, catabolized, or used in immune interactions. In normal foals receiving plasma transfusions at 1 day of age, a decrease of 30% in serum IgG concentration was observed by 7 days of age?6 This decrease may be even more profound in septic foals. Before administration, plasma should be thawed and warmed to body temperature. Previously frozen plasma should be used as soon as possible after thawing. All blood products administered intravenously should be administered through an in-line blood filter to remove fibrin strands. Even when donors have been typed and crossmatches are compatible, the initial transfusion flow rate should be slow to assess for unexpected adverse reactions. A rate of 0.1 mL/kg for 10 to 20 minutes is appropriate. This would be approximately 5 to 10 mL over 10 to 20 minutes for a 50-kg foal. During this time the recipient foal should be monitored for signs of adverse reactions. If there are no adverse reactions at this initial flow rate, the remainder of the transfusion may be administered at rates of up to 20 to 30 mL/kg/h. Slower flow rates are generally safer because transfusion reactions can be recognized before large volumes are administered. Slower infusion rates are recommended for foals with suspected or confirmed endotoxemia or septicemia. Rapid flow rates in normovolemic foals may induce iatrogenic volume overload. The foal's vital signs and behavior should be monitored throughout the transfusion and the flow rate slowed or stopped if significant changes are observed. LYMPHOSARCOMA-ASSOCIATED IMMUNODEFICIENCY
Several forms of immunodeficiency have been described in horses with lymphosarcoma. Acquired selective IgM deficiency is the most commonly described. 17, 19, 60 Affected horses may experience recurrent or persistent infections in addition to signs attributable to the underlying neoplasia. In one horse, neoplastic cells were identified as T-suppressor cells, suggesting a potential mechanism for the IgM deficiency.62 Diminished lymphocyte blastogenesis responses indicative of impaired T-cell function have been described in two horses with lymphosarcoma, one of which had concurrent IgM deficiencyP Both horses presented with
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signs of bacterial pneumonia as well as signs referable to the underlying neoplastic condition. These cases suggest that lymphosarcoma with secondary immunodeficiency should be suspected in adult horses with persistent infections that are refractory to treatment. OTHER ACQUIRED IMMUNODEFICIENCIES
There have been several reports of adult horses with presumed secondary or acquired immunodeficiencies of undetermined origin. A 7year-old Appaloosa gelding with Rhodococcus equi bacteremia and pneumonia had an absolute lymphopenia and abnormal lymphocyte blastogenesis responses consistent with impaired T-cell function. I S This gelding also had decreased serum immunoglobulin concentrations and a lack of humoral responses to vaccination consistent with impaired B-cell function. At necropsy, lymphoid tissue was depleted. Is A 3-year-old Quarter Horse with pneumonia and chronic diarrhea had IgM deficiency secondary to decreased B-cell numbers. Other immunoglobulin isotypes were also decreased, as was T-cell function. No evidence of lymphosarcom,a was found at necropsy.46 DRUG-INDUCED IMMUNE SUPPRESSION
Secondary immunosuppression can occur as a result of administration of a drug that suppresses some aspect of the immune system, most commonly by killing or inhibiting the function of lymphocytes. Sometimes these are drugs that are being purposefully administered to suppress undesirable immune-mediated phenomena (e.g., corticosteroids for treatment of immune-mediated hemolytic anemia); at other times, these are adverse drug reactions encountered while treating other illnesses (e.g., chemotherapy for treatment of neoplastic disease processes). Corticosteroids are the most frequently incriminated therapeutic agent in causing drug-induced immune suppression. In horses, corticosteroids may be used for the treatment of a variety of ailments including immune-mediated diseases, chronic obstructive pulmonary and reactive airway diseases, myositis, neurologic disorders, and shock states. Immunosuppressive doses of corticosteroids can exacerbate pre-existing infectious diseases 36 or decrease resistance to environmental pathogens. 48 Corticosteroids are potent anti-inflammatory agents whose effects are mediated through binding to intracytoplasmic steroid receptors. Steroid-receptor complexes are transported to the nucleus where they bind cellular DNA regulatory sequences and alter gene expression to enhance or inhibit specific protein production. The exact mechanisms by which corticosteroids inhibit immune function are unclear. Corticosteroids induce a lymphopenia by either lymphocyte lysis (mouse, rat, rabbit) or redistribution of circulating lymphocytes to lymphoid organs
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such as lymph nodes, bone marrow, and spleen (humans and most domestic animals).16 They are suppressive to macrophage phagocytic function, impair the killing of ingested organisms, impair secretion of monokines, and inhibit antigen processing and presentation. 16, 71 Cellmediated immunity is impaired through a variety of mechanisms including T-cell lymphopenia, suppression of proliferation in response to mitogen stimulation, altered patterns of cytokine production, and decreased antigen presentation. Humoral immunity is impaired indirectly through alterations in T-cell responses, enhanced catabolism of immunoglobulins, and decreased antigen presentation. 16 A variety of chemotherapeutic agents and other drugs that are widely used in humans and small animals have the potential to markedly suppress immune function with resultant secondary infections; however, these drugs are not used frequently in horses. Chemotherapeutic agents for the treatment of neoplasia are often cytotoxic to mature and developing lymphocytes, neutrophils, and mononuclear phagocytes, and therapy with these agents almost always is associated with a period of immunosuppression. MISCELLANEOUS CAUSES OF IMMUNE SUPPRESSION
Many viral infections transiently suppress local or systemic immune responses or both,56 predisposing to secondary infections. Chronic fungal or parasitic infections also may lead to immune suppression. Severe septicemia or endotoxemia may impair cell-mediated immune responses and decrease neutrophil numbers and bactericidal function. Patients with advanced neoplastic disease are susceptible to infections because of impaired cell-mediated and humoral immune responses. This may be the result of an abnormal bone marrow environment negatively affecting lymphocyte maturation, abnormal patterns of cytokine production and release, or impaired proliferative response caused by anergy. Severe bone marrow infiltrative disease impairs immune function by decreasing the numbers of neutrophils and having adverse effects on lymphocyte maturation processes. Protein-calorie malnutrition similarly is associated with impaired immune function and increased susceptibility to infection. Other metabolic disturbances, including a variety of vitamin and/ or mineral deficiencies also may adversely affect immune function. Exercise stress may transiently impair neutrophil antimicrobial functions, predisposing to infection. 78 Other forms of stress such as prolonged transport also may have negative effects on immune function. SUMMARY
FPT of immunoglobulin in foals is the commonest form of acquired immunodeficiency in horses. FPT predisposes foals to bacterial ihfections
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and septicemia and easily is preventable and treatable if breeding farms and veterinarians are attentive to optimum foaling management practices. Other forms of acquired immunodeficiencies are uncommon in horses, although immune function may be transiently suppressed by a wide variety of drugs, infections, or other conditions. As immunologic testing becomes more sophisticated and more readily available to equine practitioners, acquired immunodeficiencies are likely to be characterized more frequently in horses. References 1. Baird AN, Pugh DG, Rupp GP, et al: Detection of immunoglobulin G in the neonate. Equine Vet Sci 7:124-129, 1987 2. Baldwin JL, Cooper WL, Vanderwall DK, et al: Prevalence (treatment days) and severity of illness in hypogammaglobulinemic and normogammaglobulinemic foals. J Am Vet Med Assoc 198:423--428, 1991 3. Bauer IE, Brooks TP: Immunoturbidimetric quantification of serum immunoglobulin G concentration in foals. Am J Vet Res 51:1211-1214, 1990 4. Beetson SA, Hilbert BJ, Mills IN: The use of the glutaraldehyde coagulation test of· detection of hypogammaglobulinaemia in neonatal foals . Aust Vet J 62:279-281, 1985 ' 5. Bertone H, Jones RL, Curtis CR: Evaluation of a kit for determination of serum immunoglobulin G concentration in foals. J Vet Intern Med 2:181-183, 1988 6. Besser TE, Gay Ce, McGuire Te, et al: Passive immunity to bovine rotavirus infection associated with transfer of serum antibody into the intestinal lumen. J Virol 62:22382242,1988 7. Besser TE, McGuire TC, Gay CC, et al: Transfer of functional immunoglobulin G (IgG) antibody into the gastrointestinal tract accounts for IgG clearance in calves. J Virol 62:2234-2237, 1988 8. Brewer BD, Koterba AM: Bacterial isolates and susceptibility patterns in foals in a neonatal intensive care unit. Compendium on Continuing Education for the Practicing Veterinarian 12:1773-1781, 1990 9. Burton Se, Hintz HF, Kernen MJ, et al: Lyophilized hyperimmune equine serum as a source of antibodies for neonatal foals. Am J Vet Res 42:308-310, 1981 10. Carrick JB, Pollitt Ce, Thompson HL, et al: Failure of the administration of ACTH to affect the absorption of colostral immunoglobulin in neonatal foals. Equine Vet J 19:545--547, 1987 11. Cash RSG: Colostral quality determined by refractometry. Equine Veterinary Education 11:36-38, 1999 12. Clabough DL, Conboy HS, Roberts MC: Comparison of four screening techniques for the diagnosis of equine neonatal hypogammaglobulinemia. J Am Vet Med Assoc 194:1717-1720, 1989 13. Clabough DL, Levine JF, Grant GL, et al: Factors associated with failure of passive transfer of colostral antibodies in Standardbred foals. J Vet Intern Med 5:335-340, 1991 14. Clabough DL: Factors associated with failure of passive transfer in Standardbred foals. Proceedings of the American College of Veterinary Internal Medicine 8:555--558, 1990 15. Cohen ND: Causes of and farm management factors associated with disease and death in foals. J Am Vet Med Assoc 204:1644-1651, 1994 16. Cohn LA: The influence of corticosteroids on host defense mechanisms. J Vet Intern Med 5:95--104, 1991 17. Dopson Le, Reed SM, Roth JA, et al: Immunosuppression associated with lymphosarcoma in two horses. J Am Vet Med Assoc 183:1239-1241, 1983 18. Freestone JF, Hietala S, Moulton J, et al: Acquired immunodeficiency in a seven-yearold horse. J Am Vet Med Assoc 190:689-691, 1987 19. Furr M, Crisman M, Robertson J: Immunodeficiency associated with lymphosarcoma in a horse. J Am Vet Med Assoc 201:307-309, 1992
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SELLON
20. Gillette DD, Filkins M: Factors affecting antibody transfer in the newborn puppy. Am J Physiol 210:419--422, 1966 21. Grosvenor CE, Picciano MF, Baumrucker CR: Hormones and growth factors in milk. Endocr Rev 14:710-728, 1993 22. Halliday R: Failure of some Hill lambs to absorb maternal gammaglobulin. Nature 205:614, 1965 23. Higgins WP, Gillespie JH, Robson DS: Studies of maternally-acquired antibodies in the foal to equine influenza Al and Au and equine rhinopneumonitis. Equine Veterinary Science 7:207-210, 1987 24. Hodgin Ee, McGuire Te, Perryman LE: Evaluation of delayed hypersensitivity responses in normal horses and immunodeficient foals. Am J Vet Res 39:1161-1167, 1978 25. Holmes MA, Lunn DP: A study of bovine and equine immunoglobulin levels in pony foals fed bovine colostrum. Equine Vet J 23:116-118, 1991 26. Ingram DG, Smith AN: Immunological responses of young animals: 1. Review of the literature. Can Vet J 6:194-204, 1965 27. Jan CL: Cellular components of mammary secretions and neonatal immunity: A review. Vet Res 27:403--416, 1996 28. Jeffcott LB: Passive immunity and its transfer with special reference to the horse. Bioi Rev 47:439--464, 1972 29. Jeffcott LB, Jeffcott TJ: Studies on passive immunity in the foal: 3. The characterisation and significance of neonatal proteinuria. Journal of Comparative Pathology 84:455, 1974c 30. Jeffcott LB: Duration of permeability of the intestine to macromolecules in the newlyborn foal. Vet Rec 88:340-341, 1971 31. Jeffcott LB: Studies on passive immunity in the foal: 2. The absorption of 125I-Iabelled PVP (polyvinyl pyrrolidone) by the neonatal intestine. Journal of Comparative Pathology 84:279-289, 1974b 32. Jeffcott LB: Studies on passive immunity in the foal: 1. Gammaglobulin and antibody variations associated with the maternal transfer of immunity and the onset of active immunity. Journal of Comparative Pathology 84:93-101, 1974 33. Jeffcott LB: The transfer of passive immunity to the foal and its relation to immune status after birth. J Reprod Fertil Suppl 23:727-733, 1975 34. Jones D, Brook D: Investigation of the Gamma-Check-C test as a means of evaluating IgG levels in equine colostrum. Equine Veterinary Science 15:269-271, 1995 35. Kohn CW, Knight D, Hueston W, et al: Colostral and serum IgG, IgA, and IgM concentrations in Standardbred mares and their foals at parturition. J Am Vet Med Assoc 195:64-68, 1989 36. Kono Y, Hirasawa K, Fukunaga Y, et al: Recrudescence of equine infectious anemia by treatment with immunosuppressive drugs. National Institute of Animal Health Quarterly (Tokyo) 16:8-15, 1976 37. Koterba AM, Brewer B, Drummond WH: Prevention and control of infection. Vet Clin North Am Equine Pract 1:41-50, 1985 38. Koterba AM, Brewer BD, Tarplee FA: Clinical and clinicopathological characteristics of the septicemic neonatal foal: Review of 38 cases. Equine Vet J 16:376-382, 1984 39. Lavoie JP, Spensley MS, Smith BP, et al: Complement activity and selected hematologic variables in newborn foals fed bovine colostrum. Am J Vet Res 50:1532-1536, 1989a 40. Lavoie JP, Spensley MS, Smith BP, et al: Absorption of bovine colostral immunoglobulins G and M in newborn foals. Am J Vet Res 50:1598-1603, 1989b 41. LeBlanc MM, Hurtgen JP, Lyle S: A modified zinc sulfate turbidity test for the detection of immune status in newly born foals. Equine Veterinary Science 10:36--40, 1990 42. LeBlanc MM, McLaurin BI, Boswell R: Relationships among serum immunoglobulin concentration in foals, colostral specific gravity, and colostral immunoglobulin concentration. J Am Vet Med Assoc 189:57-60, 1986 43. LeBlanc MM, Tran T, Baldwin JL, et al: Factors that influence passive transfer of immunoglobulins in foals. J Am Vet Med Assoc 200:179-183, 1992 44. LeBlanc MM: Immunologic considerations. In Koterba AM, Drummond WH, Kosch PC (eds): Equine Clinical Neonatology. Philadelphia, Lea & Febiger, 1990, pp 275-294 45. Liu IKM, Brown e, Myers RC, et al: Evaluation of intravenous administration of
SECONDARY IMMUNODEFICIENCIES OF HORSES
46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.
129
concentrated immunoglobulin G to colostrum-deprived foals. Am J Vet Res 52:709712, 1991 MacLeay JM, Ames TR, Hayden OW, et al: Acquired B lymphocyte deficiency and chronic enterocolitis in a 3-year-old Quarter Horse. Vet Immunol Immunopathol 57:4957, 1997 Madigan JE: Method for preventing neonatal septicemia, the leading cause of death in the neonatal foal. Proc Am Assoc Equine Pract 43:17-19, 1997 Mair TS: Bacterial pneumonia associated with corticosteroid therapy in three horses. Vet Rec 138:205-207, 1996 Martin BR, Larson KA: Immune response of equine fetus to coliphage T2 . Am J Vet Res 34:1363-1364, 1973 McGuire TC, Crawford TB, Hallowell AL, et al: Failure of colostral immunoglobulin transfer as an explanation for most infections and neonatal deaths in foals. J Am Vet Med Assoc 170:1302-1304, 1977 McGuire TC, Crawford TB: Passive immunity in the foal: Measurement of immunoglobulin classes and specific antibody. Am J Vet Res 34:1299-1303, 1973 McGuire TC, Poppie MJ, Banks KL: Hypogammaglobulinemia predisposing to infection in foals. J Am Vet Med Assoc 166:71-75, 1975 Morgan DO, Bryans JT, Mock RE: Immunoglobulins produced by the antigenized equine fetus. J Reprod Fertil Suppl 23:735-738, 1975 Morris DO, Meirs DA, Merryman GS: Passive transfer failure in horses: Incidence and causative factors on a breeding farm. Am J Vet Res 46:2294-2299, 1985 , Nathanielsz PW, Comline RS, Silver M, et al: Cortisol metabolism in the fetal and , neonatal sheep. J Reprod Fertil Suppl 16:39-59, 1972 Olsen RG: Immune dysfunctions associated with viral infections. Compendium on Continuing Education for the Practicing Veterinarian 6:422-427, 1984 Pearson RC, Hallowell AL, Bayly WM, et al: Times of appearance and disappearance of colostral IgG in the mare. Am J Vet Res 45:186--190, 1984 Perryman LE, Buening GM, McGuire TC, et al: Fetal tissue transplantation for immunotherapy of combined immunodeficiency in horses. Clin Immunol Immunopathol 12:238-251, 1979 Perryman LE, McGuire TC, Torbeck RL: Ontogeny of lymphocyte function in the equine fetus. Am J Vet Res 41:1197-1200, 1980 Perryman LE, McGuire TC: Evaluation for immune system failure in horses and ponies. J Am Vet Med Assoc 76:1374-1377, 1980a Perryman LE: Immunological management of young foals. Compendium on Continuing Education for the Practicing Veterinarian 3(suppl):223-228, 1981 Perryman LE, Wyatt CR, Magnuson NS: Biochemical and functional characterization of lymphocytes from a horse with lymphosarcoma and igM deficiency. Comp Immunol Microbiol Infect Dis 7:53-62, 1984 Pugh DG, White SL: Commercially available tests for identification of the colostrumdeficient foal. Equine Practice 9:8-11, 1987 Raidal SL: The incidence and consequences of failure of passive transfer of immunity on a Thoroughbred breeding farm. Aust Vet J 73:201-206, 1996 Reilly WJ, Macdougall OF: The metabolism of IgG in the newborn foal. Res Vet Sci 14:136--137, 1973 Rejnek J, Prokesova L, Sterzl J, et al: The presence of IgG and IgM in full term horse umbilical cord sera. Immunochemistry 10:397-399, 1973 Robinson JA, Allen GK, Green EM, et al: A prospective study of septicaemia in colostrum-deprived foals. Equine Vet J 25:214-219, 1993 Rouse BT, Ingram DG: The total protein and immunoglobulin profile of equine colostrum and milk. Immunology 19:901-907, 1970 Rouse BT: The immunoglobulins of adult equine and foal sera: A quantitative study. Br Vet J 127:45-52, 1971 Rumbaugh GE, Ardans AA, Ginno 0, et al: Measurement of neonatal equine immunoglobulins for assessment of colostral immunoglobulin transfer: Comparison of single radial immunodiffusion with the zinc sulfate turbidity test, serum electrophoresis,
130
71. 72. 73. 74. 75. 76. 77. 78. 79. 80.
SELLON
refractometry for total serum protein, and the sodium sulfite precipitation test. J Am Vet Med Assoc 172:321-325, 1978 Schaffner A, Schaffner T: Glucocorticoid-induced impairment of macrophage antimicrobial activity: Mechanisms and dependence on the state of activation. Reviews of Infectious Diseases 9(suppl):620-629, 1987 Tizard I: In Veterinary Immunology, An Introduction, ed 3. Philadelphia, WE Saunders, 1987, p 171 Townsend HGG, Tabel H, Bristol FM: Induction of parturition in mares: Effect on passive transfer of immunity to foals. J Am Vet Med Assoc 182:255-257, 1983 Vivrette SL, Young K Manning S, et al: Efficacy of seramune in the treatment of failure of passive transfer in foals. Proceedings of the American Association of Equine Practitioners 44:136-137, 1998 Waelchli RO, Hassig M, Eggenberger E, et al: Relationships of total protein, specific gravity, viscosity, refractive index and latex agglutination to immunoglobulin G concentration in mare colostrum. Equine Vet J 22:39-42, 1990 White S: Exogenous IgG in the treatment of foals with failure of passive transfer and / or sepsis. Proceedings of the American College of Veterinary Internal Medicine 6:145-147, 1988 White S: The use of plasma in foals with failure of passive transfer and / or sepsis. Proceedings of the American Association of Equine Practitioners 35:215-218, 1989 Wong CW, Smith SE, Thong YH, et al: Effects of exercise stress on various immune functions in horses. Am J Vet Res 53:1414-1417, 1992 XU RJ: Development of the newborn GI tract and its relation to colostrum/milk intake: A review. Reprod Fertil Dev 8:35-48, 1996 Zou S, Brady HA, Hurley WL: Protective factors in mammary gland secretions during the periparturient period in the mare. J Equine Veterinary Science 18:184-188, 1998
Address reprint requests to Debra C. Sellon, DVM, PhD Department of Veterinary Clinical Sciences College of Veterinary Medicine Washington State University Pullman, WA 99164 e-mail: [email protected]