The immune system of normal foals is fairly well developed in utero; however, Colostrum and Oral Immunoglobulin Therapy in Newborn Foals FOCAL POINT

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1 286 Vol. 23, No. 3 March 2001 CE Article #6 (1.5 contact hours) Refereed Peer Review FOCAL POINT Intake of colostral IgG or a suitable substitute is essential for foals because they are susceptible to a wide range of pathogenic organisms at birth. KEY FACTS Equine and bovine colostrum can be administered to foals and provides antimicrobial and protective factors in addition to immunoglobulins, p When equine colostrum is not available, alternate sources of immunoglobulin must be sought to minimize the risk of septicemia in neonatal foals, p The serum IgG concentration can be determined in foals as young as 12 hours of age, p The amount of colostrum or substitute to be administered should not be determined based on volume but rather on the quantity of IgG in the product, p Colostrum and Oral Immunoglobulin Therapy in Newborn Foals North Carolina State University Sally Vivrette, DVM, PhD ABSTRACT: Failure of passive transfer (FPT) and partial failure of passive transfer (PFPT) are known risk factors for neonatal septicemia in foals. Colostrum from a foal s dam is ideal for treating FPT and PFPT, but equine colostrum from a source other than the dam, bovine colostrum, or a commercially available substitute may also be administered. Immunoglobulins can be absorbed by foals up to approximately 24 hours of age. Many factors can influence IgG absorption from colostrum in neonatal mammals. Serum IgG concentrations should be rechecked 8 to 12 hours after treating FPT or PFPT to assess adequacy of immunoglobulin therapy. Oral administration of immunoglobulins may be less expensive than is intravenous administration. The immune system of normal foals is fairly well developed in utero; however, little antibody production occurs before birth because of the absence of antigenic stimulation. 1 The diffuse epitheliochorial placenta of horses prevents passage of large molecules such as immunoglobulins from mares to foals. Therefore, at birth foals are essentially agammaglobulinemic (although measurable quantities of IgM and trace quantities of IgG may be present in blood samples taken from the foal before colostrum ingestion). Although newborn foals are immunocompetent, they require 10 to 14 days to mount an effective, specific response to antigens. 1 Thus newborn foals are susceptible to a wide range of pathogenic organisms, and intake of colostral IgG or a suitable colostral substitute is essential for protection against pathogens. The level of intake and the consequent serum IgG concentration that is protective have not been determined for foals and probably vary with the level of challenge. A common recommendation is to achieve a minimum serum IgG concentration of 400 to 800 mg/dl. Concentrations greater than 800 mg/dl are optimal. Failure of passive transfer (FPT; IgG less than 200 mg/dl) and partial failure of passive transfer (PFPT; IgG 200 to 800 mg/dl) are known risk factors for infection in neonatal foals. 2 When oral immunoglobulin absorption is still possible (in foals younger than 24 hours of age), FPT and PFPT may be treated by administering colostrum

2 Compendium March 2001 Equine 287 TABLE I Colostral IgG Concentrations in Mares Breeds Colostral IgG Concentration (mg/dl) Thoroughbred, ,014 quarter horse, (mean, 11,324 ± 4119) 10 saddlebred, Morgan, standardbred Quarter horse, ,000 standardbred, Arabian (mean, 16,538 ± 3618) 11 Thoroughbred Arabian 11, from other mares or giving a substitute product. The use and efficacy of these products are the subjects of this article. COLOSTRUM Good-quality colostrum is the ideal therapy for FPT in newborn foals. Although many focus on IgG as its most important constituent, colostrum contains a wide variety of factors that provide local and systemic protection against infection for newborn foals. Various constituents (including complement, lactoferrin, lactoperoxidase, and lysozyme) inhibit bacterial colonization in the intestine; colostral leukocytes also have a local protective role. 3,4 Moreover, colostrum contains growth factors and hormones that promote enterocyte maturation. 5 Thus, in addition to providing immunoglobulins, colostrum contains factors that provide local protection and potentiate gut closure. 6 When available, colostrum from a foal s dam is ideal for treating FPT and PFPT. Colostrum may also be obtained from colostrum banks maintained by some veterinary clinics and horse-breeding farms. 7 Banked colostrum (approximately 250 ml) is collected from healthy mares immediately after normal foaling (term delivery, no complications) before their foals have nursed. An estimate of the IgG concentration should be made by measuring the specific gravity of the colostrum using a colostrometer or an alcohol or sugar refractometer. 8 The specific gravity of colostrum used in a colostrum bank should be at least Colostrum donor mares should be negative for equine infectious anemia, and the colostrum should be free of anti-erythrocyte antibodies. Reported ranges for colostrum production in normal mares vary from 2.3 ± 4.9 L 10 to 5.1 ± 0.5 L. 11 The IgG concentration in colostrum also varies considerably among mares (Table I) These data highlight the IgG (mg/dl) Dose of IgG (g) Figure 1 Results of serum immunoglobulin concentrations after administering different doses of lyophilized IgG to newborn colostrum-deprived foals. 16 The orange bar represents an atypical finding in one foal. importance of estimating the IgG concentration in colostrum intended for foals with FPT. The minimum quantity of colostrum that foals must receive to prevent neonatal septicemia has not been determined but almost certainly depends on the IgG concentration in the colostrum. In calves, the minimum recommended dose of IgG is 100 g. 13 Based on studies using various doses of IgG, it has been recommended that the minimum quantity of immunoglobulin that a foal with FPT should receive to achieve serum IgG levels of 400 mg/dl or higher is 70 g. 14 COLOSTRUM SUBSTITUTES Equine Products Lyophilized Immunoglobulin Lyophilized equine immunoglobulin administration has been studied in newborn colostrum-deprived foals. In one study, 3.5 g/kg of lyophilized equine immunoglobulin, prepared by ammonium sulfate precipitation, was administered by nasogastric tube to pony foals. 15 At 36 hours of age, serum IgG levels in the foals averaged 557 mg/dl (range, 200 to 800 mg/dl). Two foals had transient diarrhea for 24 hours after receiving the lyophilized immunoglobulins. In a second study, doses ranging from 10 to 60 g of lyophilized equine immunoglobulins, prepared by ion exchange, were administered to 13 colostrum-deprived foals as a single or divided dose. Serum IgG concentrations were somewhat dose related, except in one foal that received 20 g of IgG (Figure 1). 16 The high serum IgG concentration in this foal (1200 mg/dl) suggested that it may have been incompletely muzzled after birth. The other foal had much lower IgG levels. A third study evaluated a commercially available lyophilized equine IgG product (Lyphomune, BIOQUAL, Inc., Rockville, MD) in 20 I g G CONCENTRATION MINIMUM QUANTITY OF IMMUNOGLOBULIN STUDIES IN FOALS

3 288 Equine Compendium March 2001 colostrum-deprived foals. 14 The foals received 50 to 70 g of IgG by nasogastric tube at different dosing frequencies. The serum IgG concentration was below 450 mg/dl in all the study foals, and 10 of the foals even received mare s colostrum at 24 hours of age. All foals in this study were clinically healthy. Concentrated Serum Product A concentrated equine serum product (Seramune, Sera, Inc., Shawnee Mission, KS) is marketed as therapy for FPT in foals. This product was evaluated during a study in which serum IgG concentrations were determined in foals born to 14 mares receiving five times the recommended oral dose (5.5 mg/kg) of domperidone beginning 30 days before giving birth as part of an FDA safety study. 17 The treated mares had marked premature lactation but underwent full-term, normal, spontaneous parturition. Milk was collected from each mare at foaling to determine colostral quality. Colostral specific gravity was below for all mares, and the average colostral IgG concentration, determined by radial immunodiffusion, was 1359 ± 1299 mg/dl. All foals born to these mares stood and nursed within 4 hours of birth and were given two 150-ml doses of Seramune via nasogastric tube 1 to 2 hours apart. Blood samples were collected until the foals were 12 weeks of age. Serum IgG concentrations in the study foals at birth and at 12 hours, 24 hours, and 7 days of age were lower than were the detection limits of the assay (100 mg/dl; Figure 2). Two study foals were excluded from consideration because one was very weak at birth and received intravenous (IV) plasma and oral Seramune and blood sample collection from the other was insufficient. Blood from three control foals (whose mares received no domperidone) averaged 3967 ± 1965 mg/dl IgG at 24 hours and 3300 ± 2262 mg/dl IgG at 2 weeks of age. The control foals, housed at a separate site, experienced no illness during the neonatal period. Two of the study foals were lethargic at birth and slow to nurse, two had mild diarrhea, and one had moderate joint effusion and lameness in the stifle. These five foals were treated with antibiotics for 3 to 6 days (oral trimethoprim sulfamethoxazole [20 mg/kg every 12 hours]; intramuscular [IM] procaine penicillin [22,000 U/kg every 12 hours] and IM gentamicin [10 mg/kg/day]; or IM ampicillin [20 mg/kg every 6 hours]). All foals survived to weaning and had no long-term health problems. The manufacturer of Seramune provided us with the total IgG content of the product used in our study. Each bottle contained 10 g of IgG per 300 ml. The recommended minimum quantity of IgG that foals with FPT must receive to achieve serum levels of 400 mg/dl or higher is approximately 70 g. The quantity of IgG in IgG (mg/dl) Days Figure 2 Mean serum IgG concentrations of foals that received 300 ml of Seramune (Sera, Inc., Shawnee Mission, KS; containing 10 g of IgG) at birth. The foals were born to mares that had marked loss of colostrum before foaling subsequent to receiving high doses of domperidone. The horizontal line at 100 mg/dl represents the detection limits of the assay. T-bars indicate ± standard deviation. the single bottles of Seramune given to our foals was clearly insufficient to treat FPT. Since our study was completed, the IgG concentration of Seramune has been increased to approximately 25 g/300-ml bottle. Bovine Products When equine colostrum is not available, alternate sources of immunoglobulin must be sought to minimize the risk of septicemia in neonatal foals. Few studies have evaluated colostrum from nonequine species as colostrum substitutes in foals. Colostrum In one study evaluating bovine colostrum administration in five colostrum-deprived newborn foals, serum IgG concentrations of 1350 to 3300 mg/dl were observed after foals ingested 4 L of first-milking bovine colostrum. Foals appeared slightly lethargic during colostrum administration, but this resolved when they were permitted to nurse from their mares. One foal developed mild diarrhea that resolved without treatment, and one developed an Actinobacillus septicemia that resolved with antimicrobial therapy. 18 In similar studies, mild, transient diarrhea was observed in a few foals given bovine colostrum. 19 The half-life of bovine IgG in the foals was 7 to 9 days (compared with 26 days for IgG from equine colostrum) 18,19 ; endogenous IgG production was evident by 28 to 42 days after birth. There were no long-term health problems in foals that received bovine colostrum. The results of these studies suggest that bovine IgG does provide some protection against septicemia in newborn foals. EQUINE SERUM ALTERNATE SOURCES OF IMMUNOGLOBULIN I g G PRODUCTION

4 Compendium March 2001 Equine 289 Cheese-Whey Derived Immunoglobulins Products containing cheese-whey derived bovine immunoglobulins have been evaluated as colostrum substitutes in foals. 20 Six neonatal foals, colostrum deprived at birth, received approximately 186 g of bovine immunoglobulins orally. At 3 days of age, the average serum (bovine) IgG concentration was 577 mg/dl. Two of the six foals developed localized infections, one of which required antimicrobial therapy. All treated and control group foals survived. FACTORS INFLUENCING IMMUNOGLOBULIN G ABSORPTION Many factors can influence IgG absorption from colostrum in neonatal mammals. A very important factor is the timing of colostral intake with respect to intestinal permeability, although there appears to be species differences: Foals A study by Raidal and coworkers 21 showed that neonatal foals consuming a glucose-containing electrolyte solution or milk replacer during the first 12 hours of life, followed by colostrum feeding during the next 7 hours, had serum IgG concentrations between 400 and 800 mg/dl (mean, 670 mg/dl) at 36 hours after birth. No significant differences were detected between foals fed the glucose-containing electrolyte solution or milk replacer. Calves The period during which colostrum is absorbed is approximately 24 hours. 22 Delaying the feeding of colostrum until 24 hours of age may delay gut closure and impermeability to IgG in some calves up to 33 hours. However, if colostrum is not fed until the calf is 12 hours of age, gut closure may have advanced such that no IgG absorption can take place after colostrum ingestion. 22 Early noncolostrum milk ingestion in calves does not affect intestinal permeability to colostral macromolecules. 23 Piglets The ability to absorb immunoglobulins may be retained for up to 106 hours after birth when milk products are withheld, 24 but immunoglobulin absorption is reduced if milk replacer is fed before colostrum feeding. 25 The differences in the effects of milk ingestion on colostral immunoglobulin absorption may be important when choosing the optimal treatment for FPT. Although the intestines may remain permeable to immunoglobulins for many hours after birth, feeding colostrum as soon as possible is desirable because transepithelial migration of live Escherichia coli has been demonstrated in neonatal calves before colostrum feeding. 26 The practice of ensuring colostrum ingestion before foals are 7 hours of age has been proposed by Madigan. 6 In farm situations in which illness is observed early in the neonatal period or following a difficult delivery, administering colostrum by nasogastric tube before the foal first stands may be advisable. Other factors may impact colostrum absorption. In calves, natural suckling of the dam resulted in higher serum immunoglobulin levels than did bottle feeding or esophageal feeding of colostrum. The presence of the dam may enhance colostrum ingestion. Prematurity and associated immaturity of the intestinal epithelium as well as prolonged dystocia with neonatal asphyxia may have adverse effects on colostrum absorption. 27 Elevated corticosteroid levels, associated with either stress or exogenous administration, do not appear to decrease intestinal immunoglobulin absorption in calves. Certain stresses may even enhance immunoglobulin absorption. However, administering long-acting corticosteroids to pregnant dams may cause premature maturation of the fetal intestinal tract, resulting in immunoglobulin impermeability. 27 Efficiency of immunoglobulin absorption from colostrum in one study of neonatal foals was 56.9%. 21 In comparison, absorption values between 12% 28 and 65% 29 have been reported in calves. This wide variation likely reflects differences in study methods and correction for extravascular losses, plasma expansion, immunoglobulin distribution in the extracellular pool, and calculating the volume of immunoglobulin fed. 29 Absorption of commercially available colostrum substitutes derived from bovine colostrum or cheese whey has been studied in calves. Compared with fresh colostrum, colostrum substitutes had very poor absorption (21% versus 7%, respectively). 30 In that study, calves fed colostrum substitutes had a significantly higher prevalence of illness (enteritis and respiratory disease) compared with those fed fresh colostrum. IMMUNOGLOBULIN THERAPY IN FOALS Failure of passive transfer may be suspected or assumed in situations involving agalactia, death of the mare, or inability of the foal to nurse (e.g., as a consequence of flexor tendon contracture). In these cases, and when FPT or PFPT is documented, oral immunoglobulin therapy may be instituted in foals younger than 24 hours of age. In foals that nurse normally, the serum IgG concentration may be evaluated as soon as 12 hours after birth. 10 This practice is especially important if there is any reason to suspect that foals may be at risk for FPT or PFPT. If insufficient serum IgG levels are identified, foals may be treated with equine or bovine colostrum or a substitute. IV therapy may be used, but oral therapy is often more convenient for equine practitioners. EFFECTS OF MILK INGESTION IMMUNOGLOBULIN ABSORPTION EVALUATING Ig G CONCENTRATION

5 290 Equine Compendium March 2001 Oral therapy simply involves administering colostrum or a colostrum substitute by nasogastric tube; large volumes (e.g., 1 L or more) may need to be administered in two or more doses. Syringe feeding or bottle feeding colostrum to a recumbent foal is not advised because it may put the foal at risk for developing aspiration pneumonia. IV therapy may require thawing frozen equine plasma or collecting blood from a suitable donor (free of anti-erythrocyte antibodies and negative for equine infectious anemia). Either of these procedures can take 1 to 2 hours. Alternatively, commercially available immunoglobulin supplements designed for IV administration may be used. For IV therapy, a jugular or cephalic catheter should be placed aseptically and the foal monitored for transfusion reaction (trembling, tachycardia, tachypnea, piloerection, hives). The amount of colostrum or substitute to be administered should not be determined based on volume but rather on the quantity of IgG in the product. It may be advisable to follow the recommendations used in calves: A minimum dose of 70 g of IgG should be administered when FPT is documented or suspected in foals younger than 24 hours of age. Foals with PFPT may require less IgG. Precisely calculating an appropriate dose of IgG to treat FPT or PFPT is difficult because of the potential variability in efficiency of immunoglobulin absorption as observed in calves. After treating FPT or PFPT, serum IgG concentrations should be rechecked in 8 to 12 hours to assess the adequacy of immunoglobulin therapy. If a foal still has suboptimal serum IgG levels, options can be discussed with the owner or farm manager. For foals at high risk for developing septicemia (dystocia, trouble rising, contact with sick foals on the premises), IV plasma therapy may be advised. Parenteral antibiotic treatment may also be instituted. In some cases, additional treatment may not be necessary. However, such foals should be watched closely for signs of sepsis (e.g., lethargy, diarrhea, failure to nurse vigorously). About the Author Dr. Vivrette is affiliated with the Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh. She is a Diplomate of the American College of Veterinary Internal Medicine. ACKNOWLEDGMENTS The study investigating the efficacy of Seramune in treating FPT was funded by the Department of Food Animal and Equine Medicine, College of Veterinary Medicine, North Carolina State University. The author thanks Dr. Christine King for her assistance in preparing this manuscript. REFERENCES 1. Perryman LE: Immunological management of young foals. Compend Contin Educ Pract Vet 3:S223 S228, Hines MT: Immunodeficiencies of foals, in Robinson NE (ed): Current Therapy in Equine Medicine, ed 4. Philadelphia, WB Saunders Co, 1997, pp Reiter B: Review of nonspecific antimicrobial factors in colostrum. Ann Rech Vet 9: , Ojofeitimi EO, Elegbe IA: The effect of early initiation of colostrum feeding on proliferation of intestinal bacteria in neonates. Clin Pediatr 21:39 42, Heird WC, Schwarz SM, Hansen IH: Colostrum-induced enteric mucosal growth in Beagle puppies. Pediatr Res 18: , Madigan JE: Method for preventing neonatal septicemia, the leading cause of death in the neonatal foal. Proc 43rd Annu Conv Am Assoc Equine Pract:17 19, Kubiak J, Vivrette SL: Equine colostrum: Collection, storage and utilization. Raleigh, North Carolina State University ANS publication H, Feb 15, Chavatte P, Clement F, Cash R, Grongnet JF: Field determination of colostrum quality by using a novel, practical method. Proc 44th AAEP: , LeBlanc MM, McLaurin BI, Boswell R: Relationships among serum immunoglobulin concentration in foals, colostral specific gravity, and colostral immunoglobulin concentration. JAVMA 189:57 60, Massey RE, LeBlanc M, Klapstein EF, et al: Colostrum feeding of foals and colostrum banking. Proc AAEP:1 8, Lavoie JP, Spensley MS, Smith BP, Mihalyi J: Colostral volume and immunoglobulin G and M determination in mares. Am J Vet Res 50(4): , Pearson RC, Hallowell AL, Bayly WM, et al: Times of appearance and disappearance of colostral IgG in the mare. Am J Vet Res 45(1): , McGirk S: Colostrum: Quality and quantity. Proc 17th World Buiatr Cong 2: , Franz LC, Landon JC, Lopes LA, et al: Oral and intravenous immunoglobulin therapy in neonatal foals. Eq Vet J 23: , Divers TJ, Byars TD, George LW: Lyophilized immunoglobulins as a means of passive transfer of antibodies in foals. Proc AAEP: , Shideler RK, Squires EL, Mifflin RE, Lance WR: Evaluation of lyophilized IgG as an oral supplement for failure of passive transfer in foals. Proc 33rd AAEP: , Vivrette SL, Young K, Manning S, et al: Efficacy of Seramune in the treatment of failure of passive transfer in foals. Proc 44th Annu AAEP: , Lavoie JP, Spensley MS, Smith BP, Mihalyi J: Absorption of bovine colostral immunoglobulins G and M in newborn foals. Am J Vet Res 50(9): , Holmes MA, Lunn DP: A study of bovine and equine immunoglobulin levels in pony foals fed bovine colostrum. Eq Vet J 23: , Hunt E, Van Camp SD, Hunt LD, Anderson KL: Absorption of cheese-whey derived bovine immunoglobulins in the foal. Proc 11th ACVIM Forum:961, QUANTITY OF Ig G RECHECKING Ig G CONCENTRATIONS ANTIBIOTIC TREATMENT

6 Compendium March 2001 Equine Raidal SL, McTaggart C, Yovich JV, Penhale J: Effect of withholding macromolecules on the duration of intestinal permeability to colostral IgG in foals. Proc 46 th Annu AAEP : , Stott GH, Marx DB, Menefee BE, Nightengale GT: Colostral immunoglobulin transfer in calves. I. Period of absorption. J Dairy Sci 62: , Michanek P, Ventorp M, Westrom B: Milk intake before first colostrum in newborn dairy calves. Effect on intestinal transmission of macromolecules. J Dairy Sci 73: , Payne LC, Marsh CL: Gammaglobulin absorption in the baby pig: The non-selective absorption of heterologous globulins and factors influencing absorption time. J Nutr 76: , Vellenga L, Wensing Th, Breukink JH: Effect of feeding 5 percent glucose solution or milk replacer to newborn piglets on intestinal permeability to macromolecules. Vet Rec 123: , Corley LD, Staley TE, Bush LJ, Jones EW: Influence of colostrum on transepithelial movement of Escherichia coli O55. J Dairy Sci 60: , Aldridge B, Garry F, Adams R: Role of colostral transfer in neonatal calf management: Failure of acquisition of passive immunity. Compend Contin Educ Pract Vet 14: , Balfour WE, Comline RS: Acceleration of the absorption of unchanged globulin in the newborn calf by factors in colostrum. J Physiol 160: , McEwan AD, Fisher EW, Selman IE: An estimation of the efficiency of the absorption of immune globulins from colostrum by newborn calves. Res Vet Sci 11: , Garry FB, Adams R, Cattell MB, Dinsmore RP: Comparison of passive immunoglobulin transfer to dairy calves fed colostrum or commercially available colostral-supplement products. JAVMA 1: , ARTICLE #6 CE TEST The article you have read qualifies for 1.5 contact hours of Continuing Education Credit from the Auburn University College of Veterinary Medicine. Choose the one best answer to each of the following questions; then mark your answers on the test form inserted in Compendium. 1. Which of the following statements regarding the use of bovine colostrum in treating foals with FPT is correct? a. Bovine colostrum does not provide adequate immunoglobulin to aid in preventing neonatal septicemia. b. Bovine colostrum should not be used in foals. c. Bovine immunoglobulins have a shorter half-life in foals than do equine immunoglobulins. d. No adverse effects are associated with administering bovine colostrum. 2. The minimal specific gravity of colostrum maintained in a colostrum bank is a c b d In normal newborn foals, serum IgG concentrations can be evaluated as soon as hours of age. a. 6 c. 18 b. 12 d may adversely affect IgG absorption from colostrum in neonatal calves. a. Elevated endogenous corticosteroids b. Prematurity c. Early noncolostrum milk ingestion d. Ingestion of colostrum before 2 hours of age 5. Orally administering the concentrated serum product Seramune a. is ineffective at treating FPT in foals. b. may be effective at treating FPT if a sufficient dose of immunoglobulin is administered. c. is not useful. d. is effective in raising serum IgG levels to greater than 800 mg/dl after administering one bottle (300 ml) to foals with FPT. 6. The minimum dose of IgG that a foal with FPT should receive is g. a. 50 c. 70 b. 25 d The amount of colostrum that normal mares produce is approximately L. a. 1 c. 7.5 b. 3 d The IgG concentration in colostrum obtained from normal mares a. is the same for all breeds of horses. b. ranges from 200 to 800 mg/dl. c. averages approximately 11,000 mg/dl. d. can be determined by evaluating the viscosity of the colostrum. 9. Plasma for IV administration to foals a. can be administered through an IV catheter with monitoring for transfusion reactions. b. can be obtained from mares that have anti-erythrocyte antibodies. c. should not be used if oral immunoglobulin is available. d. is the only source of IV immunoglobulin therapy for foals. 10. The absorption efficiency of oral immunoglobulins for neonatal foals younger than 24 hours of age is %. a. 15 c. 56 b. 27 d. 72