Definition and Etiology

Normal foals are immunocompetent at birth (i.e., they are capable of mounting an immune response). However, they are immunologically naive in that they have had no exposure to foreign antigens and have therefore not yet mounted any type of protective immune response or accumulated significant levels of immunoglobulins. Although foals are capable of producing antibody, they are essentially devoid of immunoglobulin at birth, with the exception of small amounts of IgM normally produced in utero. Because they are “starting from scratch,” foals are indeed more susceptible to infectious agents during the early neonatal period. Foals begin producing immunoglobulins immediately on exposure to antigens after birth, and immunoglobulins produced by the foal are detectable within 1 to 2 weeks of life and reach significant levels by 2 months.

Under normal circumstances, temporary protection against infection for the first 1 to 2 months is provided to the foal in the form of passively transferred antibody (Fig. 53-3). Because of the diffuse epitheliochorial nature of the equine placenta, no transplacental transfer of immunoglobulins occurs in horses. Instead, ingestion and absorption of immunoglobulin-rich colostrum are the sole means of passive transfer in foals. In a properly functioning system, maternal antibodies wane as levels of autologous antibodies increase, and thus the neonate is never left totally unprotected (Fig. 53-4).

Fig. 53-3 The duration of protection provided by maternal immunoglobulins varies with the class of immunoglobulin and the quantity ingested during the first 24 hours of life.

Fig. 53-4 Maternal immunoglobulin wanes, whereas the production of autologous immunoglobulin increases during the first several months of life. The combined total amount of immunoglobulin ideally remains above the level considered minimum for maintenance of good health.

Failure of the foal to ingest or absorb sufficient quantities of colostrum, primarily as defined by absorption of IgG, is termed failure of passive transfer (FPT). Complete FPT is defined as a foal with a serum IgG concentration of less than 400 mg/dL at 24 hours of age. Partial FPT is defined as a foal with a serum IgG concentration of 400 to 800 mg/dL at 24 hours of age. The reported incidence of complete or partial FPT in foals varies from 3% to 37.8%.^18-25

Immunoglobulins are not produced locally in the mammary gland, but rather are selectively concentrated from the mare’s sera into colostrum in response to hormonal changes that occur in the last 2 weeks of pregnancy. Most immunoglobulin in equine colostrum is IgG or IgG(T), with smaller quantities of IgM and IgA. At birth the neonate has specialized enterocytes in the gastrointestinal (GI) tract that are able to absorb large molecules such as immunoglobulins intact by pinocytosis. Absorbed proteins pass through the intercellular spaces and lacteals into the systemic circulation via the lymph. The window of gut absorptive capacity for immunoglobulins is narrow, lasting from birth until about 18 to 24 hours. Maximal absorptive efficiency occurs immediately after birth, declining to only 22% efficiency at 3 hours after birth and less than 1% by 20 hours.^26,27 The decline in immunoglobulin absorption is accompanied by transient proteinuria that peaks at 6 to 12 hours of age and declines by 24 to 36 hours of age. This proteinuria most likely reflects absorption and excretion of low—molecular-weight milk proteins.²⁸

Diminished immunoglobulin absorption over the first 12-24 hours of life is the result of shedding of specialized enterocytes capable of pinocytosis and replacement by more mature cells that are incapable of absorbing immunoglobulins.^26,27,29 It has been hypothesized that delayed ingestion of macromolecules may prolong the duration of intestinal permeability to immunoglobulins. In one study, however, the type of fluid administered to foals before the ingestion of colostrum did not influence subsequent IgG absorption, suggesting that the process of gut closure is not mediated by a finite capacity for the uptake of macromolecules.³⁰

The half-life for maternal antibodies in the foal’s circulation varies between 20 and 30 days.^31-33 Concentrations decline as a result of normal protein catabolism, gradual dilution in an increasing plasma volume as the foal grows, and transfer of functional antibody into the GI tract. Most maternal antibodies are present in only negligible concentrations by 6 months of age, although antibodies to some infectious agents have been detected for up to 12 months after birth. As passive antibody concentrations decline, autogenous antibody production begins. There is a nadir in serum immunoglobulin concentrations in colostrum-fed foals at approximately 1 to 2 months of age, followed by gradually increasing concentrations until adult levels are reached at 5 to 10 months.^2,34 Serum immunoglobulin concentrations are similar in colostrum-fed and colostrum-deprived foals by 3 to 4 months of age.

In addition to antibody, other colostral factors may be important for optimal immune protection of foals. For example, colostrum influences cell-mediated immunity and activates granulocytes. Colostrum contains many constituents of innate immunity and immunomodulating agents, such as complement, cytokines, and trace elements, that have a local protective effect in the neonatal digestive tract.^35,36

In foals, FPT may occur because of ingestion of poor-quality colostrum with a low immunoglobulin content, failure to ingest a sufficient quantity of colostrum, or failure to absorb colostral immunoglobulins from the GI tract.^29,37 Colostrum may have an insufficient quantity of immunoglobulin because of prelactation (lactation before parturition), premature foaling, a defect in the mare’s ability to concentrate immunoglobulin in the colostrum, ingestion of endophyte-contaminated fescue grass or hay, or other factors. Mares most likely to produce colostrum with low immunoglobulin content are those older than 15 years of age, those that foal early in the year, and standardbred mares.

Foals that are orphaned or rejected at birth, too weak to stand, or unable or lack the desire to suckle are unlikely to ingest sufficient colostrum to prevent FPT. Malabsorption is occasionally incriminated as a cause of FPT in foals that are observed to suckle adequate quantities of good-quality colostrum. This most often happens in premature or dysmature foals, possibly as a result of immature GI function, but may also occur in otherwise healthy and vigorous full-term foals.³⁸ Glucocorticoids enhance the maturation of small-intestinal epithelial cells and thus their loss of absorptive capacity, leading to speculation that endogenous corticosteroids released secondary to stress at parturition may impair immunoglobulin absorption in foals.^39,40 However, administration of adrenocorticotropic hormone (ACTH) failed to affect absorption in experimental foals, and stress has not been a consistent historic finding in foals with FPT caused by presumptive impaired immunoglobulin absorption.^22,41

Clinical Signs and Differential Diagnoses

The association between FPT and infection has been investigated in numerous studies.^18-20,24,25 Although the results have varied somewhat, FPT is generally considered a risk factor for infectious disease. By itself, FPT produces no clinical signs of disease and cannot be detected by physical examination. Clinical presentations that strongly suggest an underlying problem with FPT include onset of bacterial infections within the first 2 weeks of life, particularly septicemia, septic arthritis, pneumonia, and enteritis. Other immunodeficiencies or simply exposure to potent pathogens cannot be ruled out solely on the basis of the time of onset; however, even with other forms of immunodeficiency, clinical signs of infection usually do not show up for several weeks if passive transfer is adequate.

Clinical Pathology

FPT is diagnosed by the demonstration of low serum concentrations of IgG in the foal as early as 6 to 12 hours after birth and probably for as long as several weeks after birth (Table 53-1). The level of IgG considered adequate for protection against infectious disease is poorly defined and probably varies considerably with the environment. A serum IgG concentration greater than 800 mg/dL is considered adequate for most foals. However, levels of 400 mg/dL may be sufficient in healthy foals housed in clean environments. In contrast, an IgG concentration of 400 to 800 mg/dL in a foal at high risk for sepsis because of its environment or other factors indicates the need for treatment. Importantly, these figures only address total immunoglobulin content and not specific antibody titers, which also play a critical role in determining resistance to particular pathogens.

Table 53-1 Normal Serum Immunoglobulin Concentrations (mg/dL) in Horses

In healthy foals that nurse within 2 hours of birth, serum IgG concentrations become detectable at approximately 6 hours of age and peak at approximately 18 hours. Routine determination of serum IgG concentrations in apparently healthy foals is usually recommended at 18 to 24 hours of age. Foals considered to be at high risk for FPT and sepsis may be assessed as early as 6 to 12 hours of age.^35,42

Methods available for IgG quantitation include single radial immunodiffusion, zinc sulfate turbidity, latex agglutination, glutaraldehyde coagulation, turbidometric immunoassay, and enzyme immunoassay.^11,35,43-47 Single radial immunodiffusion is considered the most quantitatively accurate diagnostic test of those widely available to practitioners. However, this test is more expensive than some other screening tests, and results are not available for at least 24 hours, making it impractical when a critically ill foal needs rapid diagnosis and treatment. Total serum protein is not a reliable indicator of FPT in foals (unlike calves) because of the wide variation in total serum protein in cases of adequate transfer.

No consistent changes in the hemogram and biochemical panel are seen in foals with FPT; however, a range of abnormalities related to secondary infection (e.g., neutrophilia, neutropenia), hyperfibrinogenemia, and hypoglycemia may be present. The presence and severity of these changes depend on the organisms and systems involved.

Necropsy Findings

No specific necropsy findings are indicative of FPT. Necropsy findings reflect the site and severity of secondary infectious problems that have developed. Lymphoid tissue is normally developed, unless secondary infections have caused lymphoid necrosis or atrophy.

Treatment and Prognosis

Treatment of FPT depends on the degree of FPT, the environment in which the foal is exposed, the foal’s age at diagnosis, and the presence of secondary infectious problems. Treatment is aimed at minimizing exposure to pathogens, supplying immunoglobulins, and managing secondary infections, if present.

If FPT can be anticipated within hours of birth because of premature lactation, low—specific gravity colostrum, or a weak or orphaned foal, treatment can include the provision of an alternative source of colostrum or antibody orally. Foals with complete colostrum deprivation require approximately 1.5 g IgG/kg body weight to achieve a peak serum IgG concentration of more than 800 mg/dL. In a 45-kg foal, administration of 1 to 3 L of colostrum with a specific gravity greater than 1.060, divided into multiple hourly feedings over the first 6 to 8 hours of life, is desirable. Mares that donate colostrum for feeding should be healthy, checked for blood type, negative for anti—red blood cell (RBC) alloantibodies (especially anti-A and anti-Q) and appropriately vaccinated during the last 4 to 6 weeks of gestation.

If equine donor colostrum is not available, bovine colostrum, a commercial colostrum substitute, or equine plasma may be administered orally to the foal.^48-55 Because bovine colostrum is often more readily available than equine colostrum, it may be substituted in emergency situations when equine colostrum is not available. Bovine colostrum is relatively well absorbed in the foal, but bovine immunoglobulins have a much shorter half-life in foals and do not contain antibodies specifically directed against equine pathogens. It is certainly better than no colostrum and, on the basis of a small experimental study, may be used without creating adverse reactions.^48-50 Approximately 2 to 4 L should be administered orally; many foals develop transient mild diarrhea.

Lyophilized equine IgG* is available as an equine colostral substitute. A minimum of 50 to 70 g of IgG is recommended for treatment of the average 45-kg foal that receives no colostrum, but in one study this dose failed to increase serum IgG concentration to over 450 mg/dL in colostrum-deprived foals.⁵⁵ A concentrated equine serum product† is also available for use in foals with FPT.⁵⁶ Again, however, in one study it failed to increase serum IgG concentrations in colostrum-deprived foals to adequate levels, probably because of the relatively low total IgG dose administered.⁵¹ If the product contains 25 to 30 g of IgG per 300-mL bottle, approximately three bottles may be required to increase the serum IgG concentration of a 45-kg colostrum-deprived foal to greater than 400 mg/dL.⁵¹

If no other sources of immunoglobulin are available for a foal, oral administration of equine plasma or serum may be considered. This is an expensive source of oral immunoglobulin, however, and approximately 2 to 4 L are required to treat a colostrum-deprived 45-kg foal.

If the foal is over 6 hours old, the absorption of colostral antibody is significantly decreased, although a locally protective effect of the colostrum may still be present in the intestinal tract. If the foal is over 12 hours old, it is unlikely that sufficient colostrum will be absorbed; therefore, immunoglobulin levels should be rechecked at 24 hours and intravenous (IV) plasma transfusion given, if indicated by persistently low serum immunoglobulin levels.

Some animals with FPT, particularly partial FPT, do well without treatment if they are systemically healthy, are not heavily exposed to pathogens, and have no preexisting infections. FPT itself is not necessarily fatal. If plasma transfusions are not administered, owners should be made aware of the risks, and these foals should be maintained in an environment with minimal exposure to potential pathogens. Foals with other risk factors for septicemia (e.g., prematurity, dysmaturity, placentitis) should receive IV plasma transfusions if they have blood IgG concentrations of less than 800 mg/dL at 12 to 24 hours of age.

If the decision is made to supplement plasma parenterally, equine plasma for transfusions is commercially available† or can be collected and processed locally. Commercial sources are convenient, save time, have been screened for anti-RBC antibody, are free of diseases such as equine infectious anemia, and originate from animals with known immunoglobulin levels. The major disadvantage is that plasma may not contain antibody specific for the pathogens from the particular environment to which the foal is exposed.

Use of a local donor is desirable in that it presumably has antibody specific to the environmental pathogens to which the foal has been exposed. If a local donor is to be selected, several criteria should be met. First, the horse should be healthy, and results of agar gel immunodiffusion for equine infectious anemia should be negative. Second, no anti-RBC antibody should be detectable in the horse’s serum. The donor’s plasma should be screened for lysins and agglutinins by a blood-typing laboratory against a panel of cells representing all known blood groups. If plasma evaluated in this way is not available, the presence of anti-RBC antibody in donor plasma can be crudely evaluated with a minor crossmatch for agglutination using donor plasma and recipient blood cells. Lytic antibodies require an external source of complement for activity in vitro and may not be detected using this test.

Ideally, a third criterion is selection of a horse that is negative for blood group factors Aa and Qa. Even though there are dozens of blood group factors, Aa and Qa have been associated with the great majority of cases of neonatal isoerythrolysis (NI).^57-59 If plasma is collected and separated by sedimentation, it is inevitable that some RBC contamination be present. If Aa-positive (Aa+) RBCs are given to an animal that is Aa negative (Aa−), or if Qa+ RBCs are given to an animal that is Qa−, the recipients could become sensitized to these antigens. This sensitization would probably not have any immediate consequences for the recipient foal, because the foal’s cells would not be affected by the antibodies, but it has potentially sensitized any Aa− and Qa− females for production of an NI foal later (see p. 1685). To avoid these potential complications, the ideal donor should be Aa− and Qa− and possess no anti-RBC antibody in its serum. It is desirable to have identified this type of donor to avoid the need for immediate crossmatching in every case of plasma transfusion.

The volume of plasma needed to correct the measured IgG deficit in a foal can theoretically be calculated on the basis of the blood volume of the foal and the concentration of IgG in the foal’s serum and in the donor plasma; however, these calculations do not reliably predict the actual levels of IgG achieved after transfusion.^35,60 A 20-mL volume of plasma per kilogram of body weight administered intravenously routinely only raises serum IgG levels 200 to 300 mg/dL, and often two to three times this amount is needed to bring serum IgG levels into the range considered minimum for protection (e.g., 400 to 800 mg/dL).^35,61 If the foal is already clinically ill, additional plasma will often be required to raise IgG levels an equivalent amount.^35,44 In a newborn foal (estimated 50 kg) with complete FPT, between 2 and 4 L of plasma is frequently needed.

Plasma should be administered through an IV catheter placed aseptically in one jugular vein. Frozen plasma is thawed and warmed slowly to room temperature in a warm water bath. Microwave thawing or thawing with very high temperatures is not recommended because this may denature important plasma proteins. An appropriate in-line blood filter should be used for IV administration of any blood product to remove fibrin clumps and other debris. Initial infusion rates should be slow (0.5 mL/kg over 10 to 20 minutes) to monitor for adverse reactions. Muscle fasciculations, piloerection, increased heart or respiratory rate, fever, respiratory distress, abdominal pain, blanching of mucous membranes, and collapse are indicative of transfusion reactions. In the absence of these or other adverse effects, the remainder of the transfusion may be administered at rates up to 40 mL/kg/hr. Slower infusion rates are recommended for foals that are systemically ill. If other IV fluid therapy is being administered concurrently, slower infusion rates are also indicated to diminish the likelihood of inadvertent fluid overload.

Serum IgG concentrations in the foal should be rechecked 12 to 24 hours after plasma transfusion to confirm that the desired increase has been achieved. The delay from transfusion to IgG assessment is necessary to allow for distribution of immunoglobulin into extravascular spaces. Healthy foals transfused with plasma at 1 day of age experienced a 30% decrease in serum IgG concentrations by 7 days of age.⁶² This decline might be even more dramatic in septic foals with increased vascular permeability, increased catabolism, and increased demand for utilization in immune responses.

Although several equine serum-derived products are marketed for IV administration in the treatment of foals with FPT, these products have been associated with significant adverse reactions in some foals. Administration of high-quality equine plasma is preferred for treatment of foals with FPT.

Prevention and Control

Evaluation of colostral immunoglobulin content has proved to be valuable in predicting the occurrence of FPT and assessing the neonate’s risk for FPT.^35,63 Colostrum with high immunoglobulin concentration tends to be sticky, yellow, and thick, but these subjective criteria are unreliable in assessing colostral quality. The quantity of immunoglobulin in colostrum may be more accurately estimated by single radial immunodiffusion (RID), refractometry, glutaraldehyde coagulation, or specific gravity.⁶² Because 18 hours are required to read the results of RID, it is more practical in a field situation to assess specific gravity with a refractometer, glutaraldehyde coagulation test or colostrometer. Sugar refractometry using a hand-held Brix 0-50% sugar refractometer is a simple and cost-efficient stall-side screening test for assessing colostral quality.^64,65 A Brix reading of 20% to 30% correlates with adequate colostral quality; a reading greater than 30% indicates good-quality colostrum.⁶⁶ A commercial kit based on glutaraldehyde coagulation of immunoglobulins* is available for screening of colostral quality. Using a colostrometer,† colostral specific gravity should be a minimum of 1.060, corresponding to an IgG concentration of greater than 3000 mg/dL; levels of 6000 mg/dL or higher are desirable. Approximately 75% of foals that ingest colostrum with a specific gravity less than 1.060 will have serum IgG concentrations under 400 mg/dL; when colostral specific gravity is greater than 1.060, foals usually attain serum IgG concentrations above 500 mg/dL.⁶³

Some of the causes of FPT can be alleviated or recognized for early intervention by careful management. These include identification of mares that drip colostrum before parturition, attendance at foaling to ensure that foals suckle within several hours of birth or are supplemented artificially with colostrum, and screening of high-risk foals with doubtful nursing histories. Routine screening of foals at 18 to 24 hours of age allows early identification of FPT and potentially allows for therapy before the onset of infections. Although signs of septicemia secondary to FPT are often first observed on day 3 to 4 of life, a bacteremia may already be present at 24 hours of age or earlier.^66,67

A colostrum bank can be established by collecting small amounts of colostrum from lactating mares (e.g., 200 to 250 mL) within the first 3 to 6 hours after foaling. This is only about 10% of the total colostrum produced by the average mare in the first 20 hours after parturition and therefore does not adversely affect the foal suckling the donor mare. Although the volumes are quite variable, mares produce about 300 mL of colostrum per hour and about 5 L during the first 18 hours. Colostrum can be stored frozen for at least 1 year at standard freezer temperatures, approximately −20° C (−4° F). Although frozen immunoglobulins are stable for much longer, the overall quality of the colostrum may deteriorate. Ideally, banked colostrum should be screened for the presence of anti-RBC antibodies as advised for plasma. Colostrum typically has low titers of agglutinins, which are probably not of significance unless present a dilutions of 1/8 or greater.

Definition and Etiology

Severe combined immunodeficiency (SCID) is a lethal, inherited condition in which both T-cell and B-cell function is absent.⁶⁸ Affected foals have a stem cell defect that prevents maturation of T and B cells, resulting in a complete inability to produce antigen-specific immune responses. The condition primarily affects Arabians and part Arabians, although sporadic cases have been described in other breeds.^68,69 In horses of Arabian breeding, the condition is transmitted as an autosomal recessive trait.⁷⁰ Carriers of the gene are asymptomatic but can now be detected by genetic testing.⁷¹

Clinical Signs and Differential Diagnoses

Foals that are homozygous for the defective SCID gene are clinically affected. These foals generally appear physically normal at birth, but the absence of both specific humoral and cellular immune responses renders them susceptible to infections once colostral protection wanes.⁶⁸ Affected foals typically develop infectious diseases between birth and 2 months of age and die before 5 months of age. The age of onset of infectious disease depends to some degree on the adequacy of passive transfer and the environmental challenge by organisms. The infections in affected animals are nonspecific and are caused by a variety of bacterial, viral, parasitic, and fungal agents, some of which rarely affect animals that are not immunocompromised.^68,72,73 Many body systems may be involved, but pneumonia is a particularly common feature. Pneumocystis carinii pneumonia and adenoviral pneumonia are found often in SCID foals and rarely in other foals.

Clinical Pathology

A consistent finding on the hemogram is an absolute lymphopenia, which is consistently less than 1000 lymphocytes/μL and often much lower. The total white blood cell (WBC) count may be low, normal, or elevated, depending on the neutrophilic response; thus it is imperative that the absolute number of lymphocytes be determined. Infected and other compromised foals, as well as some normal foals, have low lymphocyte counts during the first few days of life; therefore, the clinician should establish persistent lymphopenia before considering a diagnosis of SCID.^68,74

Foals affected with SCID are unable to produce immunoglobulins. Therefore, levels of autologous serum immunoglobulin for age are abnormally low. However, quantitative immunoglobulin tests do not distinguish between autologously produced and maternal-origin immunoglobulin. Thus the degree of colostral transfer and the age of the foal must be considered when interpreting the serum immunoglobulin values (see Table 53-1). Some IgM is normally produced in utero by the foal, and some IgM should be present in presuckle serum.⁷⁵ Although not pathognomonic, the absence of IgM in presuckle serum is a feature of SCID. The presence of colostral antibody of maternal origin may mask low levels of autologous IgG and IgM, particularly early in life. The levels of maternal IgM in colostrum are lower than IgG, and the half-life of IgM is shorter (Table 53-2). Most maternal IgM received from colostrum is metabolized by about 3 weeks of age, whereas the age at which maternal IgG is gone is much more variable and may actually be months, depending on the original amount absorbed. The absence of serum IgM after 3 weeks of age is not pathognomonic but is consistent with SCID.

Table 53-2 Approximate Half-Life (in Days) of Immunoglobulin Classes in Large Animals

Foals affected with SCID do not respond to intradermal phytohemagglutinin (see p. 1667) by increasing skin thickness as do normal foals, nor do they respond to DTH stimulators, such as dinitrochlorobenzene.⁷⁶ In vitro tests such as blastogenesis are depressed with all mitogens.^77,78

The definitive diagnosis of SCID in foals of Arabian breeding is based on demonstrating that the foal is homozygous for the defective SCID gene.^71,79 Blood or cheek swabs may be submitted to VetGen for DNA testing to determine if a horse is clear, heterozygous, or homozygous for the gene defect. Before the advent of genetic testing, the criteria required to confirm a diagnosis of SCID included (1) persistent lymphopenia (<1000/μL), (2) absence of serum IgM in presuckle samples or samples collected after 3 weeks of age, and (3) thymic hypoplasia and characteristic histopathologic changes in lymphoid tissue.^80,81

Pathophysiology

Foals with SCID lack activity of the enzyme DNA-dependent protein kinase (DNA-PK) resulting from a mutation in the gene encoding the catalytic subunit.^79,82,83 The mutation results in a five—base-pair deletion in the gene on equine chromosome 9. Without functional DNA-PK, lymphocyte precursors are unable to complete gene rearrangement events that lead to the expression of antigen-specific receptors on lymphocyte surfaces. As a result, there is an absence of mature, functional T and B lymphocytes. Interferon-γ (EqIFN-γ), which is produced by lymphocytes, is deficient.⁸⁴

Neutrophils, monocytes, and natural killer (NK) cells appear to be fully functional.^85,86 Complement levels are normal.⁷⁸ Although these nonspecific protective mechanisms appear to be intact, the absence of both cell-mediated and antibody-mediated immunity leaves the foal vulnerable to even innocuous infectious agents.

Epidemiology

SCID has been reported in Arabians in the United States, Canada, Australia, and Great Britain.^68,87,88 It is believed that the trait originated in a horse in Great Britain and was subsequently imported into the United States. The distribution of this disease provides a significant example of the founder effect in population genetics.

The prevalence of SCID at one time was estimated to be 2% to 3% of Arabian foals born in the United States. From this, it was predicted that the numbers of SCID carriers at that time could be as high as 25% of the U.S. Arabian horse population. A 1998 study of 250 randomly selected Arabian horses in the United States found the frequency of SCID gene carriers to be 8.4%.⁸⁸ Based on this finding, it was predicted that 0.18% of Arabian foals would be affected with SCID, assuming a random breeding population.

Necropsy Findings

It is imperative to evaluate lymphoid tissues grossly and histologically in cases of suspected immunodeficiencies. In SCID the thymus is small and has a fatty appearance on gross examination.⁸⁰ It is frequently difficult to locate, and mediastinal tissue often must be collected “blindly” for subsequent histologic evaluation and identification of thymic remnants. Histologically, the thymus is largely replaced with adipose tissue, with only islands of lymphoid cells and partially formed Hassall’s corpuscles present. The gross appearance of spleen and lymph nodes may not be dramatically abnormal; however, they have very abnormal microscopic appearances, including absence of germinal centers and periarteriolar lymphocytic sheaths in the spleen, as well as absence of germinal centers with scarcity of lymphocytes in other areas of lymph nodes.

Bronchopneumonia is a common finding in SCID. Infectious lesions in other systems are also frequently found, including colitis and hepatitis.

Treatment and Prognosis

Affected foals invariably die by about 5 months of age, despite intensive conventional therapy (e.g., antimicrobials, plasma, isolation).

There is no practical method of curing affected foals at this time. Successful bone marrow transplants have been performed between histocompatible full siblings in a research setting, but this option remains impractical.⁸⁹

Prevention and Control

Production of an affected foal identifies both sire and dam as carriers of the SCID gene.⁷⁰ Mating of two carriers of an autosomal recessive trait such as SCID is expected to result in one in four foals affected with SCID, one in four completely normal and not a carrier, and two in four asymptomatic carriers of the SCID trait. Mating of a carrier and a normal (noncarrier) does not produce any affected foals, but half the offspring would be expected to be carriers.

The disease can be controlled in horses of Arabian breeding by avoiding the production of affected foals, which has been simplified now that carriers can be identified by genetic testing. Mares and stallions intended for breeding should be tested to determine whether they are free or heterozygous for the defective SCID gene. Under no circumstances should two heterozygotes be mated to each other. If an owner decides to continue breeding a heterozygote, the breeding partner should be confirmed homozygous normal. All foals from such matings should be tested to determine if they are clear of or heterozygous for the defective gene (50/50 probability). Homozygous normal foals may be selected for future breeding purposes, whereas heterozygous foals should be managed for nonreproductive pursuits.

Definition and Etiology

Selective IgM deficiency is an immunologic disorder characterized by absent or decreased serum IgM levels with normal or elevated levels of other immunoglobulin classes. Three presentations of the disorder have been described in horses.^90-93 The most common involves foals that have severe infectious pneumonia, arthritis, or enteritis, resulting in death before 10 months of age. The second involves foals with a history of repeated episodes of infections that respond to antimicrobial therapy but that recur when treatment is stopped. These foals tend to do poorly and are stunted, although they may survive for 1 to 2 years. The third involves older horses that are usually 2 to 5 years of age at initial diagnosis. These horses do not necessarily have problems with recurrent infections, but about half ultimately have lymphosarcoma.⁹⁴

It is not known whether the IgM deficiencies reported in foals are primary or secondary. The levels of IgM present before the onset of infections have not been measured. The occurrence of multiple cases within groups of related horses suggests a genetic basis. However, breeding trials have been inconclusive to date with regard to the heritability of this condition. In humans, both primary and secondary selective IgM deficiencies are known. Secondary cases are often associated with neoplasia, immunologic diseases such as Wiskott-Aldrich syndrome, and gluten-sensitive enteropathies.

Clinical Signs and Differential Diagnoses

Foals with selective IgM deficiency tend to have frequent Klebsiella infections of the respiratory tract, although enteritis and septic arthritis may also be complicating infections. The age of onset of clinical signs may be slightly later than in foals with SCID and certainly later than in foals with FPT.

Older horses with IgM deficiency should be carefully evaluated for lymphoid neoplasia, including palpation of peripheral and internal lymph nodes. Weight loss, depression, and other nonspecific signs frequently accompany lymphosarcoma (see Chapter 37).

Clinical Pathology

The only significant immunologic abnormality is a low or absent serum IgM. IgM levels are more than 2 standard deviations below the age-specific mean IgM level (see Table 53-1). Other classes of immunoglobulin are generally within normal limits or elevated for age. It is advisable to document that IgM levels are persistently depressed rather than to base a diagnosis on a single sample, because IgM levels may sporadically decrease in seriously ill foals but return to normal with recovery. Lymphocyte counts and other in vitro immunologic tests are generally normal, and these features serve to differentiate selective IgM deficiency from other immunodeficiency conditions. In one horse with selective IgM deficiency, however, lymphocytes failed to respond to the B-cell mitogen lipopolysaccharide (LPS), whereas response to the T-cell mitogens concanavalin A (ConA) and phytohemagglutinin (PHA) was normal.⁹³ The hemogram and biochemical profile may reflect infection or inflammation, depending on the underlying infectious process (e.g., neutrophilia, hyperfibrinogenemia, anemia) and the organ system involved, but no diagnostically specific changes occur.

Pathophysiology

Whether IgM is low because of decreased production, hypercatabolism, or loss is not known. In one case with lymphosarcoma, suppressor activity was identified in the neoplastic cells, suggesting that the low IgM may be a result of suppression of B-cell function by neoplastic cells. Selective IgM deficiency has been most frequently reported in Arabians and quarter horses, although it affects other breeds as well.

Necropsy Findings

Lymphoid tissue in affected foals is grossly and histologically normal. Pneumonia is usually present and is frequently caused by Klebsiella infection. Other findings reflect secondary infections.

Treatment and Prognosis

Selective IgM deficiency has an unfavorable prognosis. Most horses eventually succumb to infection despite appropriate antimicrobial therapy. Plasma therapy may provide short-term benefit, but only small amounts of IgM are contained in transfused whole plasma, and the half-life of transfused IgM is probably quite short. No concentrated IgM preparations are commercially available for parenteral use. Relief, at best, can be considered only temporary. However, the outcome of these cases seems less certain than with SCID foals, and a rare case recovers. If persistently low IgM levels can be documented, a poor to grave prognosis can be expected.

Prevention and Control

Because some cases of selective IgM deficiency might be hereditary, it may be advisable to avoid repeating the mating that produced the affected foal. However, no firm recommendations can be made.

Definition and Etiology

Transient hypogammaglobulinemia is a rare disorder characterized by the delayed onset of immunoglobulin synthesis by the neonate.^5,95 Foals normally begin to produce significant amounts of immunoglobulins at birth, when they are first exposed to environmental antigens (see Fig. 53-4). Assuming adequate passive transfer, maternal antibody fills the void from birth until the foal has produced sufficient autologous antibody for protection (e.g., first 1 to 2 months). In transient hypogammaglobulinemia the onset of autologous production is delayed for unknown reasons and may not begin for as long as 3 months. As maternal immunoglobulins wane, for a time the production of autologous antibody is insufficient to be protective, making the foal highly susceptible to infections.

The disorder has been described in an Arabian and a thoroughbred foal, but the low number of reported cases may not accurately reflect the prevalence. To make a diagnosis, serial samples are required to document decreasing maternal immunoglobulin and subsequent increasing autologous immunoglobulin. Many cases probably occur that are not followed this closely.

Clinical Signs and Differential Diagnoses

As with other immunodeficiency disorders, recurrent episodes of bacterial and viral infections are characteristic of transient hypogammaglobulinemia.

Clinical Pathology

The cardinal feature is low immunoglobulin levels.^5,23,95 At approximately 2 to 4 months of age, the concentrations of all classes of immunoglobulin, particularly IgG and IgG(T), are substantially below the means when age-matched. At this stage, maternal antibody will have waned, but the foal should have produced significant quantities of autologous antibody, regardless of whether passive transfer occurred. Affected foals have normal cell-mediated responses in vitro and in vivo and appear to be able to respond to immunization with some antigens. Normal numbers of B cells are present in blood and lymph nodes.

Differentiation between FPT and transient hypogammaglobulinemia is based on the age of the patient at evaluation. Transient hypogammaglobulinemia must be differentiated from agammaglobulinemia. Both disorders have normal lymphocyte counts and responses to PHA skin testing and show waning levels of maternal IgG and IgG(T) if followed serially. However, transient hypogammaglobulinemia cases usually have low but detectable levels of IgM and IgA, whereas agammaglobulinemia cases usually have no detectable levels. Differentiation between the two may require serial sampling to show that immunoglobulin production does ultimately increase in the patient with transient hypogammaglobulinemia.

Necropsy Findings

No specific gross or microscopic lymphoid changes have been associated with transient hypogammaglobulinemia. Necropsy findings reflect the secondary infectious processes that have affected the foal.

Treatment and Prognosis

The goal of therapy is to minimize infections until the foal’s immune system begins to function properly. Treatment should include antimicrobial therapy and plasma transfusions. Bacterial infections may be manageable with antibiotics alone, but the effects of viral infections may be more difficult to manage and may be helped by plasma transfusions.

Definition and Etiology

Agammaglobulinemia is a rare primary immunodeficiency disorder of horses. It is characterized by complete B-cell dysfunction with an intact cell-mediated response. This condition has been observed only in males, suggesting the possibility of an X-linked disorder. It has been described in thoroughbreds, quarter horses, and standardbreds.^23,96-98 Agammaglobulinemia in a young boy was the first immunodeficiency disorder described in any species, and in human patients it is now known to be inherited as an X-linked trait.⁹⁹

Horses with agammaglobulinemia illustrate the significant contribution of T and B lymphocytes to the maintenance of good health. Horses with defects in both B-cell and T-cell functions (e.g., SCID) seldom survive to 5 months of age, whereas the cases with a pure B-cell defect such as agammaglobulinemia have survived between 1 and 2 years. Recently, agammaglobulinemia with a lack of circulating B cells was diagnosed in a Pinto gelding that did not exhibit recurrent pyogenic infections until 3 years of age. Although it could not be established whether the immunodeficiency was primary or secondary, an underlying disease process was not identified.*

Clinical Signs and Differential Diagnoses

No outward physical signs suggest agammaglobulinemia other than the opportunistic infections that develop. Frequently, recurrent infections of the respiratory tract or joints with extracellular bacteria have been reported. Dermatitis, enteritis, and laminitis have also been associated with this disease.

Clinical Pathology

Total peripheral blood lymphocyte counts are within the normal range. However, there is a lack of circulating B cells with normal numbers of T cells. Neutrophil counts may be normal, low, or high, depending on the response to infection. No specific changes are noted in the biochemical profile. Serum levels of IgM, IgA, IgG(T), and IgG are persistently low or absent. Depending on the age at evaluation, maternal antibody may be present, but its decline is evident if sampled serially. The continued presence of low levels of immunoglobulin in these foals may be explained by the prolonged catabolism of antibody or by some residual B-cell activity, as in human patients with sex-linked agammaglobulinemia.^23,96-99

Specific antibody responses are depressed, both for antigens to which horses naturally tend to produce antibodies, such as sheep RBCs, and for antigens administered by planned immunization, such as vaccines. Cell-mediated tests are essentially normal, including blastogenesis and DTH skin testing. Total hemolytic complement activity is also normal.

Pathophysiology

The molecular basis of agammaglobulinemia in horses is unknown, but a defect at the stem cell level that blocks early B-cell differentiation is suspected because all classes of immunoglobulin are affected. In human patients a mutation in BTK, a gene encoding tyrosine kinase, accounts for the disease. Assessment of the BTK gene in horses may help in understanding this disorder.

Necropsy Findings

Gross lymphoid changes in lymph nodes, spleen, and thymus have been observed. Lymph nodes are small. The thymus may be small and difficult to locate. Lymphoid tissue taken from the mediastinal region where the thymus should be found lacks the defined lobular structure of normal thymus. The spleen grossly may be small and contracted. Microscopically, lymph nodes are devoid of germinal centers and follicles. The spleen has no germinal centers, periarteriolar lymphocytic sheaths, or plasma cells.

The thymus does not show recognizable epithelial structure and lacks defined nodules.^23,98 Why cell-mediated functions are normal while the architecture of the thymus is so abnormal remains unexplained.

Treatment and Prognosis

In the absence of production of autologous antibody, affected horses respond poorly to infections over the long term. Antimicrobial therapy and administration of plasma may temporarily control infections; however, the long-term prognosis is poor.

Definition and Etiology

A congenital fatal syndrome characterized primarily by severe anemia and immunodeficiency has been identified in Fell Pony foals.¹⁰⁰ In addition, peripheral ganglionopathy has been reported in some cases. Both genders are affected. The exact nature of the defect is as yet unknown, but an intrinsic genetic disorder transmitted by a single autosomal recessive gene is suspected.¹⁰¹ The Fell Pony is considered an endangered breed by the Rare Breeds Survival Trust, with an estimated 5000 animals worldwide. Originally described in Fell Ponies in the United Kingdom, Fell Pony syndrome has also been found in the Netherlands and North America.^100-102

Clinical Signs

Affected Fell Pony foals typically develop signs of decreased suckling, diarrhea, cough, and chewing motions beginning at 2 to 3 weeks of age.^100-102 The foals progressively lose condition and develop pale mucous membranes. The condition is generally fatal by 4 to 12 weeks of age. Opportunistic infections such as cryptosporidial enteritis, adenoviral pancreatitis, and adenoviral bronchopneumonia are frequently observed in affected foals and suggest an underlying immunodeficiency.

Clinical Pathology

Foals develop severe normocytic to macrocytic anemia associated with small numbers of erythroid precursor cells in the bone marrow.^100-102 Myeloid/erythroid ratios in the bone marrow have ranged from 21:1 to 62:1. Although total circulating lymphocyte counts are variable, lymphopenia is described in some cases. Numbers of both CD4⁺ and CD8⁺ T lymphocytes are normal, but numbers of B cells are decreased.^103,104 Consistent with this B-cell lymphopenia, serum immunoglobulin concentrations are often decreased once concentrations of maternal antibodies have declined.^102-104 Because maternally derived concentrations of IgM and IgA generally do not persist as long as IgG, concentrations of these antibodies are more likely to reflect production by the foal. The responses of lymphocytes to in vitro stimulation with mitogens have been variable.¹⁰⁵

At this time, no definitive test is available for the diagnosis of Fell Pony syndrome, and diagnosis is based on the signalment, history, clinical signs, and laboratory findings, including anemia, B-cell lymphopenia, and low concentrations of IgM after 4 weeks of age.

Pathophysiology

The precise nature of the immune defect is unknown, and thus far the characteristics identified do not conform to any known immunodeficiencies in other species. In addition to the decrease in circulating B cells, immunohistochemical staining reveals decreased B cells in the bone marrow, lymph nodes, and primary follicles of the spleen. Although analyses of cellular immunity and phagocytic activity have not revealed any consistent abnormalities, the severity of disease has led to speculation that multiple arms of the immune system are affected. The anemia is associated with severe erythroid hypoplasia of the bone marrow.

Necropsy Findings

The absence of secondary lymphoid follicles and lack of plasma cells on histologic examination is characteristic of the condition. There is also marked erythroid hypoplasia in the bone marrow. In some cases, peripheral ganglionopathy is seen, characterized by neuronal chromatolysis and nuclear pyknosis of the trigeminal, cranial mesenteric, or dorsal root ganglia. Other common necropsy findings include abnormalities associated with infections characteristic of immunodeficiency, particularly infections with Cryptosporidium parvum and adenoviral infections of the pancreas and bronchial tree.

Treatment and Prognosis

Affected foals respond poorly to treatment for infections and anemia.^100-102 They generally die by 12 weeks of age.

Definition and Etiology

Common variable immunodeficiency (CVID), a heterologous syndrome of immunodeficiency, has been described in four horses.^106,107 It has also been suspected in additional horses with varying immunologic deficits.^108-110 CVID was initially defined in human patients, and although the syndrome is highly variable, recurrent bacterial infections and hypogammaglobulinemia are common characteristics.^111,112 CVID has also been reported in miniature dachshunds with Pneumocystis carinii pneumonia.¹¹³

Clinical Findings

Information on CVID in horses is limited because of the small number of cases. The syndrome has been identified in various breeds and both genders and is characterized by a late onset, with horses ranging in age from 6 to 14 years.^106,107 In human patients the disorder affects both men and women and can develop at any age, although the onset is most frequently seen during the second or third decade of life.^111,112

Recurrent bacterial infection is common in CVID. Three horses with CVID diagnosed with presumptive bacterial meningitis were successfully managed medically with antibiotic therapy without immunoglobulin replacement therapy.¹⁰⁷ Another horse with CVID presented with infection of the guttural pouch and cholangiohepatitis and was ultimately euthanized because of deterioration in the horse’s condition.¹⁰⁶ The clinical spectrum of CVID in human patients is broad, and as expected, clinical disease is more severe in patients with more marked immunologic abnormalities.^111,112

Immunologic Findings

Common features of CVID in affected people include recurrent bacterial infections and agammaglobulinemia or hypogammaglobulinemia, particularly involving IgM and IgG.^111,112 The humoral response to vaccination is generally impaired. B-cell maturation may be arrested at various stages, and B-cell numbers may be normal or decreased. T-cell abnormalities may also be present. As in human patients, immunologic abnormalities identified in affected horses include hypogammaglobulinemia and failure to respond to immunization.^106,107 The type and severity of the hypogammaglobulinemia vary; IgM deficiency is common. Affected horses have an abnormal lymphocyte distribution characterized primarily by B-cell lymphopenia. The lymphocyte response to mitogens varies but generally is decreased. Phagocytosis, oxidative burst activity, and serum opsonization capacity were normal in three horses tested.

The variable immunologic abnormalities associated with CVID make it difficult to define cases, and it has been suggested that additional cases of recurrent bacterial infections and immune abnormalities may represent variations of CVID. An adult Paso Fino mare with proliferative interstitial pneumonia and Pneumocystis carinii infection was found to have a complete lack of IgM, low concentrations of IgG, and decreased numbers of immune cells expressing major histocompatibility complex (MHC) class II cell surface antigens.¹⁰⁸ In another case, a 3-year-old quarter horse with chronic diarrhea and bacterial pneumonia was diagnosed with an acquired B-lymphocyte deficiency associated with deficiencies in serum IgG, IgA, and IgM and a concurrent decrease in T-cell function.¹⁰⁹ Additional cases with hypogammaglobulinemia and other immunologic abnormalities may fit the description of CVID.^93,110,114

Adult Acquired Immunodeficiency

A 7-year-old Appaloosa gelding with no history of prior illness became lethargic, anorexic, and dyspneic.¹¹⁴Rhodococcus equi septicemia was diagnosed on the basis of blood cultures. Immunologic evaluation of the patient revealed lymphopenia, low IgM and IgA concentrations, marginally low IgG concentrations, low R. equi antibody titer, negligible response to lymphocyte stimulation, histologic depletion of the lymphoid tissue, and failure to respond to antigenic stimulation. Marked thrombocytopenia was also present. These abnormalities suggested suppression of both humoral and cell-mediated arms of the immune system. The age of the horse, absence of previous history of illness, and histopathologic findings suggestive of atrophy of lymphoid tissue indicated the immunodeficiency was acquired. No underlying cause was identified for the immunodeficiency; specifically, no neoplasms were identified at necropsy, and there was no history of exposure to immunosuppressive toxins. This may represent CVID.

Infectious Disease

Secondary immune suppression can result from a variety of infectious or inflammatory diseases. Many viral, fungal, and bacterial infections transiently suppress specific and nonspecific immune responses, predisposing to secondary bacterial infections.¹¹⁶ Severe endotoxemia or septicemia may suppress neutrophil numbers and bactericidal function.

Perinatal Equine Herpesvirus Type 1 Infection

Infection of the fetus with equine herpesvirus type 1 (EHV-1, rhinopneumonitis) late in gestation has been associated with postnatal development of interstitial pneumonia, lymphopenia, marked necrosis and atrophy of the thymus and splenic lymphoid tissue, and increased susceptibility to bacterial infections.¹¹⁷ Affected foals may be either weak or normal at birth. Despite apparently adequate passive transfer of maternal antibody, affected foals contract a variety of infectious bacterial diseases, including colibacillosis, streptococcal septicemia, salmonellosis, and Tyzzer’s disease. EHV-1 is isolated from nasal passages of about 30% of the cases. The spleen and thymus are grossly small at necropsy. Bilateral adrenocortical hyperplasia is noted in most foals. Histologically, splenic periarteriolar lymphocytic sheaths are depleted of lymphocytes, and no lymphoid follicles are detectable. Thymic alterations vary from extreme diminutions of thymocyte numbers to complete necrosis of thymic lymphocytes with disappearance of Hassall’s corpuscles and disruption of the epithelial matrix. Lymph nodes also show lymphoid necrosis.

An immunodeficiency secondary to the marked lymphoid damage induced by the virus is credited with allowing secondary bacterial infections to become established. Immunization of broodmares against EHV-1 would seem to be the most appropriate approach to prevention.

Immunodeficiency Associated with Oral Candidiasis and Bacterial Septicemia

Neoplasia

Neoplastic disease can impair cell-mediated and humoral immune responses as a result of an abnormal bone marrow environment, altered patterns of cytokine production or release, or impaired proliferative responses (anergy). In horses, immunodeficiency has most often been described in association with lymphosarcoma or plasma cell myeloma.

Definition and Etiology

At birth, ruminants leave the sterile uterus and are exposed to an environment laden with pathogens. Although capable of mounting a measurable immune response at birth or even earlier, neonates are best characterized as being “immunonaive.” A neonate’s ability to mount a protective immune response is hindered by the immaturity of the immune system and the delay between initiation of response and effective protection. Unless adequate maternal immunologic assistance is provided, neonates have an increased likelihood of succumbing to infectious diseases such as septicemia, diarrhea, enteritis, omphalitis, arthritis, and respiratory conditions.

Neonatal ruminants are protected against disease from infectious agents through passive transfer of maternal immunity by consumption of colostrum. The concept of failure of passive transfer (FPT) has largely been used to describe a neonate that does not absorb adequate levels of immunoglobulin. Immunoglobulins are a significant component of colostrum and have been the most studied constituent of colostrum. However, colostrum is a complex fluid that, in addition to immunoglobulins, contains high numbers of immune cells, immunoactive substances such as cytokines, and nutritional elements.¹⁴⁸

Successful passive transfer of immunity can be defined as the timely ingestion and absorption of an adequate mass of colostral immunoglobulins (primarily IgG1 in calves), and possibly other colostral components as well. Successful passive transfer has been quantitatively defined as calves that have attained greater than 10 mg/mL serum IgG1 by 48 hours of age.¹⁴⁹ The levels of serum immunoglobulins defining successful passive transfer are simply guidelines derived from statistical analysis of large populations. Numerous factors interact with the level of passively acquired immunoglobulin to determine the occurrence of disease, including management, environment, hygiene, infection pressure, virulence of infectious organisms, and antibody specificity. Although neonates with FPT are at increased risk for disease, having low serum immunoglobulin does not necessarily guarantee disease if the neonate resides in a clean environment or does not interact with highly virulent organisms. Alternatively, neonates with adequate passive transfer can readily develop disease if exposed to an environment with a high pathogen load or highly virulent organisms.

Mechanism of Passive Transfer

Two distinct processes must occur for adequate passive transfer of maternal immunoglobulins through colostrum. The first process, colostrogenesis, is the transport of immunoglobulin from maternal serum into colostrum during the last 4 to 6 weeks of gestation and is largely controlled by lactogenic hormones.^150-152 Studies in cattle have demonstrated that the mechanism of immunoglobulin transfer involves an active, IgG1-specific, receptor-mediated process.¹⁵³

The second process involves the transport of colostral IgG1 from the gut lumen into the neonate’s system. This process is not selective for specific immunoglobulin isotypes and does not appear to differentiate between most macromolecules. Specific receptors for immunoglobulins are absent in the calf’s gut; rather, transport occurs through nonselective pinocytosis. Absorption is initiated by the presence of macromolecules but declines over the first 24 hours of life¹⁵⁴; absorption is finite and decreases regardless of macromolecules being present.^155,156 The absorptive process also appears to be saturable; efficiency of immunoglobulin absorption decreases with increasing immunoglobulin concentration in the colostrum being fed.¹⁵⁷ Presumably, because all macromolecules compete for the same absorptive process, the mass of immunoglobulin absorbed by the calf would be inversely proportional to the concentration of nonimmunoglobulin macromolecules present in the gut lumen.

Epidemiology

The percentage in calves with FPT at 24 hours of age varies from 15% to 68%.¹⁵⁸ Similar findings have been recorded in other neonatal ruminants. In one report comparing FPT in beef calves and diary calves, rates of 5% and 39% were reported, respectively.¹⁵⁹ Several interrelated factors account for the varying incidence of FPT, including the formation of colostrum with an adequate immunoglobulin concentration, ingestion of an adequate mass of immunoglobulin, and absorption of immunoglobulin in a timely manner.

Formation of Colostrum with Adequate IgG1 Concentration

The mass of immunoglobulin presented to the neonate for absorption depends on the colostral immunoglobulin concentration and volume of colostrum available. The volume of colostrum produced by the cow is usually not a limiting factor.¹⁶⁰ However, colostrums have varying immunoglobulin concentration; IgG1 concentration in beef cow colostrum is two to three times greater than that of dairy cow colostrum.^161-164 Significant differences exist not only among different breeds but also among cattle within a specific breed.¹⁶⁵ Lactation number also influences IgG1 concentration in colostrum, although this variation is less than between cows or breeds.

Colostrum with low immunoglobulin concentration, resulting in ingestion of an inadequate mass of immunoglobulin, is a primary cause of FPT in dairy calves.¹⁶¹ In contrast, FPT in beef calves is unlikely to result from low colostral IgG1 concentration.

Ingestion of Adequate Mass of IgG1

Depending on the environment and pathogen load to which they are exposed, calves must ingest an adequate mass of IgG1 to obtain protective immunity. Although the actual mass of immunoglobulin needed for protection depends on many factors, studies suggest that for a 45-kg calf to attain a serum IgG1 concentration greater than 10 mg/mL, it must consume approximately 100 g of IgG1 in the first hours of life.¹⁶⁶ Consumption of 100 g colostral IgG1 ultimately depends on colostral volume and IgG1 concentration. A calf provided colostrum with 35 mg/mL IgG1 would need to consume approximately 3 L in the first 12 to 24 hours, whereas a calf provided colostrum with 100 mg/mL IgG1 must consume only 1 L. An accepted recommendation for attaining adequate passive transfer in diary calves is to administer 4 L of colostrum in the first 12 hours of life.¹⁶⁶

Concentration of colostral immunoglobulin is rarely a significant factor leading to FPT in beef calves. Instead, factors such as mismothering, poor udder conformation, and environmental stresses are more significant in preventing beef calves from ingesting the colostrum. Other factors that may affect passive transfer in beef calves have been reviewed.¹⁶⁷ There is little evidence to suggest a direct effect on passive transfer when beef cows are fed protein- or energy-restricted diets. Dystocia does not appear to affect passive transfer of immunoglobulins as long as the calf receives an appropriate mass of immunoglobulin in a timely manner.

Young age of the dam is a risk factor for FPT, likely because of lower colostral immunoglobulin concentration in heifer colostrum (beef and dairy) and poorer mothering ability.

Timely Absorption of IgG1 by Gut

Cessation of absorption of colostral immunoglobulins (closure) occurs at approximately 24 hours of age.^154,168 If colostrum is completely withheld, closure will still occur by 30 hours of age.^155,156 Closure is minimally affected by stresses such as dystocia or cold environmental temperatures, although extremely high environmental temperature has been associated with reduced immunoglobulin absorption in calves.^154,169 In a study comparing three different feeding methods of colostrum to dairy calves, FPT was more prevalent with sucking than artificial feeding methods, presumably because of inadequate colostrum volumes ingested by calves.¹⁶⁶ That is, dairy calves consuming relatively low IgG1 concentration colostrum did not consume adequate volumes of colostrum to obtain 100 g of IgG1 in a timely manner. When artificial feeding methods are used, inadequate immunoglobulin concentration in the colostrum is the most important factor resulting in FPT, even when calves are fed in a timely manner.

Mothering

Mothering has been associated with increased efficiency of absorption of colostral immunoglobulins. This may simply be a result of the dam’s presence or may be related to the effect of the neonate physically suckling the dam.¹⁵⁴

Clinical Signs and Laboratory Findings

Although not diagnosed by physical examination, FPT is typically suspected based on physical findings. Young ruminants devoid of passive immunity are highly susceptible to bacterial septicemia.^158,170 Clinical signs of bacteremia include central nervous system (CNS) depression, weakness, injected scleral vessels, rapid or labored respiration, diarrhea, and anorexia. Fever may or may not be present. Septic arthritis, meningitis, and panophthalmitis frequently develop in many neonates with FPT that survive the initial challenge of bacteremia. Diarrhea can also result from a number of dietary and infectious agents in neonatal ruminants with normal serum immunoglobulin levels.¹⁷¹ Historical information of clinical disease may lead to a high degree of suspicion that FPT is present.

There are no consistent changes in the hemogram or biochemical panel of a neonatal ruminant with FPT. Abnormal laboratory findings usually reflect secondary processes involving sepsis, stress, or starvation. Laboratory evaluation is necessary to assess the degree of passive transfer.

Measurement of Passive Transfer

Several methods are available to measure passive transfer of immunity either directly or indirectly. The greatest degree of accuracy is obtained if the tests are performed during the first week of life, and most tests are optimized when serum samples are collected between 24 and 48 hours of age. After this period, neonates begin to synthesize significant amounts of immunoglobulins, although a tentative decision can still be made as to the degree of passive transfer that occurred after birth. Any question about the status of passive transfer in a newborn should trigger laboratory evaluation of the animal so that corrective measures can be undertaken.

Single radial immunodiffusion (RID) quantitatively measures serum IgG1 and is considered the standard in cattle. The semiquantitative methods for estimating passive transfer (zinc sulfate turbidity, sodium sulfite precipitation, glutaraldehyde coagulation, total serum solids) are based on the fact that IgG1 normally accounts for the majority of passively transferred proteins in colostrum. Measurement of serum γ-glutamyltransferase (GGT) is based on the findings that mammary secretory alveolar epithelial cells can secrete large amounts of GGT during colostrogenesis and that GGT is readily absorbed by the neonate before gut closure.

Single Radial Immunodiffusion

Quantification of each immunoglobulin class that is transferred can be determined using specific, commercially available antisera. Forty-eight-hour serum concentrations of less than 1000, 80, and 22 mg/dL for IgG, IgM, and IgA, respectively, are consistent with FPT.¹⁶⁰

Zinc Sulfate Turbidity

Specific concentrations of zinc sulfate precipitate immunoglobulins.^149,172 Historically, a defined volume of serum (0.1 mL) is added to zinc sulfate solution (6 mL) containing 208 mg of ZnSO₄ \cdot 7H₂O per liter, and the solution is allowed to incubate at room temperature for 1 hour. The turbidity of the solution is then evaluated visually or with spectrophotometric methods.¹⁴⁹ A decrease in or an absence of turbidity (precipitation) indicates failure of immunoglobulin absorption.

A study by Tyler et al.¹⁷³ suggests that the zinc sulfate test using a 208-mg/L solution has an inappropriately high endpoint, with a specificity of only 0.52. The poor predictive value of this method results in a significant misclassification of calves with adequate passive transfer as having FPT. A follow-up study suggests that higher zinc sulfate concentrations in the test solution provide a more accurate assessment of passive transfer. As zinc sulfate concentrations are increased from 200 to 400 mg/L, sensitivity decreases from 100 to 82.6, and specificity increases from 25.5 to 90.6, respectively. The concentration of zinc sulfate test solution chosen therefore depends on the goal of the test. Choosing a test solution with higher sensitivity (e.g., 250 mg/L zinc sulfate) is likely warranted when testing individual calves with high economic value. In herd-monitoring programs, however, the choice of a test solution with higher specificity (e.g., 350 to 400 mg/L zinc sulfate) will maximize the proportion of calves correctly classified.

Sodium Sulfite Precipitation

This test is similar to the zinc sulfate turbidity test and is also a precipitation test for immunoglobulins, primarily IgG1, with the results recorded visually.¹⁷⁴ The reagents are commercially available.* Historically, three concentrations of Na₂SO₃⁻ anhydrous (14%, 16%, and 18%) are used in the test. Serum (0.1 mL) is added to each concentration of sodium sulfite (1.9 mL), and these are allowed to incubate for 1 hour. Turbidity in only the 18% sample indicates transfer of less than 500 mg/dL immunoglobulin, turbidity in both the 16% and the 18% sample indicates 500 to 1500 mg/dL of transfer, and turbidity in all samples indicates greater than 1500 mg/dL transfer.

Similar to the zinc sulfate turbidity assay, the endpoint for the sodium sulfite precipitation assay is likely set too high.¹⁷³ The preferred test endpoint appears to be a 1+ test result. A 1+ result equates to observing turbidity in the 18% test solution, with no turbidity in either the 16% or the 14% test solution. Tyler et al.¹⁷³ demonstrated the lowest serum IgG1 concentration (measured by RID) observed in calves with a 1+ test result was 645 mg/dL (range, 645 to 2450 mg/dL), indicating at least partial successful passive transfer of immunoglobulin. Therefore, it is recommended that the sodium sulfite test be used as a single-dilution assay procedure whereby calves with 1+ test results (precipitation in only the 18% test solution) are classified as having “adequate” passive transfer.

Glutaraldehyde Coagulation Test

This test is based on 10% glutaraldehyde reagent coagulating serum immunoglobulins in concentrations greater than 600 mg/dL. When performed on serum, the glutaraldehyde coagulation test is an accurate predictor of passive transfer status.^175-178 However, if whole blood is used in a similar assay, the sensitivity and specificity of the assay are deemed to be inadequate for routine diagnostic use.¹⁷⁹

Refractometer (Total Serum Solids)

Quantification of total serum solids as an indicator of passive transfer of immunity assumes that the increase in serum proteins over that of presuckle newborn ruminants is caused by the absorption of immunoglobulin.¹⁸⁰ In the absence of dehydration, serum protein concentration greater than 5.0 g/dL has historically been associated with successful passive transfer, and values less than 4.5 g/dL are consistent with FPT. Values between 4.5 and 5 g/dL are deemed questionable.

In a study of 242 calves, use of a 5.0-g/dL threshold resulted in a highly specific (0.96) but insensitive (0.59) test, whereas a 5.5-g/dL threshold resulted in a highly sensitive (0.94) but relatively nonspecific (0.76) test.¹⁷³ The choice of threshold (5.0 or 5.5 g/dL) depends on the prevalence of passive transfer in the herd being tested and the costs associated with false-positive and false-negative results. Using regression analysis to predict serum IgG1 concentration as a function of serum protein concentrations (with a goal of 10 mg/mL IgG1), the optimal threshold value for serum concentration is calculated to be 5.2 g/dL.¹⁷³

γ-Glutamyltransferase

GGT is present in colostrum at levels about 300 times higher than that normally found in serum. GGT is absorbed by the calf during the period of immunoglobulin absorption, and calf serum levels can be used as an indication of immunoglobulin absorption. Levels of GGT are maximal in the calf on the first or second day after birth.^181,182 Parish et al.¹⁸³ used a regression formula to set age-adjusted thresholds for serum GGT activity in order to define passive transfer status in dairy calves.¹⁸³ Using serum IgG1 concentration of 10 mg/mL as an acceptable goal for passive transfer of immunoglobulins, calves at 1 day, 4 days, and 7 days of age should have serum GGT activities greater than 200, 100, and 75 IU/L, respectively. Calves in the first 2 weeks of life with serum GGT levels less than 50 IU/L can be classified as having FPT.

Prevention

The intake and absorption of adequate amounts of quality colostrum are key to the survivability of young ruminants. Documented natural sucking or force-feeding of colostrum in the first 6 hours of life helps to ensure adequate transfer. It is generally thought that a neonate should consume between 6% and 10% of its body weight as colostrum in the first 24 hours of life. Most calves consume approximately 2 L (40 to 50 mL/kg) of colostrum at the first feeding. In force-feeding practices, 2 L typically has been advocated as the proper amount for initial intake. However, the variance in colostrum quality suggests that a greater volume should be fed at the initial feeding.¹⁵⁴ As stated earlier, to attain adequate passive transfer in dairy calves, the current recommendation is to administer approximately 4 L of colostrum in the first 12 hours of life.¹⁶⁶ In herds or flocks where neonatal disease is a problem, levels of passive transfer should be determined, and force-feeding of all newborn animals should be instituted to ensure adequate transfer.

Whole-colostrum specific gravity can be reasonably measured with a colostrometer.¹⁸⁴ A specific gravity less than 1.050 is associated with colostrum that has low immunoglobulin concentration. This device can eliminate 50% of the low-immunoglobulin colostrums and predict high immunoglobulin concentrations.¹⁵⁴ At colostrum temperatures other than 20° C (68° F), less accuracy is achieved.¹⁸⁵ Colostrum should contain greater than 6000 mg/dL total immunoglobulin. To ensure that all neonates receive adequate amounts of colostrum, producers should be encouraged to maintain a bank of frozen colostrum. Colostrum from first milkings is preferred because immunoglobulin concentrations decrease with successive milkings.

Immunoglobulins are generally unaltered by freezing, and only small amounts are inactivated by thawing. Thawing frozen colostrum in warm water is quickly accomplished for individual calf feeding. Microwave ovens have been used to thaw frozen colostrum without adverse effects.¹⁸⁶

Pooling or mixing colostrum from several cows is a common practice to ensure adequate immunoglobulin concentrations. This practice is advocated to circumvent the problem of low-concentration colostrum from being fed. However, calves that receive pooled colostrum acquire substantially lower serum immunoglobulin levels than calves fed equivalent volumes of homologous colostrum from their own dam.¹⁶⁰ This appears to relate to the fact that colostrums used in pooling frequently come from cows with high volumes of colostrum that tend to have lower immunoglobulin levels.¹⁸⁷

Many commercially available colostrum substitutes can be used either to supplement available colostrum or to provide a source of immunoglobulins for calves when colostrum is not available. It is important to note the amount of immunoglobulin present in these products and administer enough product to ensure passive transfer. With some products, it may not be possible or practical to administer enough colostrum substitute to obtain 100 g IgG1. Furthermore, the antibody specificity of the immunoglobulins present in these products may be unknown.

Bovine colostrum is frequently used to supplement or replace homologous sources of colostrum in nonbovine ruminants. Neonatal lambs and kids are frequently supplemented in this way.^188,189 The immunoglobulins are absorbed at rates similar to homologous colostrum. The half-life of bovine IgG1 in lambs is approximately 14 days,¹⁸⁹ which is similar to the 13.7 days reported for ovine IgG1 in lambs¹⁹⁰ (see Table 53-2). Occasionally, anemia has been reported in lambs and kids fed bovine colostrums as a result of immune complex attachment to erythrocytes, causing their removal from circulation.^191-193 The effectiveness of bovine or caprine colostrum in other species is unknown, but the practice appears to be widespread and has been used in a wild animal park successfully hand-raising neonatal exotic ruminants.

Treatment

FPT in an otherwise normal neonate can be treated with plasma administered at 20 to 40 mL/kg intravenously (or intraperitoneally if IV administration is not possible or practical). Whole blood can also be used, although the dose should be increased to account for the presence of RBCs. Similar approaches are indicated in animals with clinical disease, but the results are often less rewarding. Continued oral colostrum supplementation of neonates with FPT beyond the period of closure may also provide some local immune protection in the gut.¹⁶⁰ Some clinicians have advised oral supplementation with plasma after gut closure, but this practice is questionable in light of the cost of obtaining plasma, and plasma contains only about 15 mg/mL IgG1, significantly less than average colostrum.

Mechanisms

The cellular mechanisms responsible for the immunosuppression during pregnancy and postpartum involve (1) a shift of T-helper (Th) cells from a Th1 to a Th2 response and (2) a decrease in neutrophil functions.^213,214 The T-cell populations are affected by progesterone, prostaglandin F_2α, and α-fetoprotein.²¹¹ The Th1 cells are important effectors of the cell-mediated immune (CMI) response and interact with T-cytotoxic (Tc) cells. Tc cells are the main defense against foreign antigens, which include viral, intracellular bacterial, and protozoal pathogens. With the onset of pregnancy, the hormonal factors cause macrophages to release predominantly Th2-stimulating cytokines, which contribute to the overall dominance of humoral immunity during pregnancy and immediately postpartum. This phenomenon of the Th-cell populations is referred to as the “Th1-Th2 shift of pregnancy” and is generally regarded as a contributing factor to maternal tolerance of the fetus by suppressing the antifetal CMI response.²⁰⁹

The second key cell population affected during pregnancy and postpartum is the neutrophil.²¹² The point of maximum immunosuppression occurs when glucocorticoid levels are acutely elevated in the periparturient cow.²¹⁵ Neutrophil dysfunction, as well as the effects on the Th-cell population, is considered temporary during this period. Nonetheless, with impaired neutrophil response, the animal is then vulnerable to increased bacterial infections because of compromised bactericidal functions.²¹²

Outcome

This temporary immunodeficiency allows for fetal survival but may also result in an increased susceptibility to exterior environmental infection with viruses, bacteria, and fungi. Intracellular infections, such as with viruses and protozoans, which may have been acquired early during postnatal development, may become exacerbated during pregnancy because of the suppressive effects on the Th1 cells.²¹¹ This results in a decreased CMI response. The CMI effector cells (Tc cells) function normally to control virtually all the viral infections, such as infectious bovine rhinotracheitis virus and BVD virus.^211,216 Intracellular bacterial infections, such as Brucella abortus, become more pathogenic during pregnancy. In addition to the effects on T-cell functions, macrophage function is also compromised, allowing for opportunistic bacteria and Chlamydiophila species (usually confined to external mucosal surfaces) to become systemic. Concurrent with the immunosuppression that accompanies pregnancy, there is an increased shedding of infectious microorganisms²¹¹ (Figure 53-5). This is considered to be an extension of impaired Tc-cell function. Although the pregnant animal may appear clinically normal, her altered immune response results in an increased shedding of gastrointestinal (GI) viruses such as coronavirus and rotavirus^211,217 and bacteria (Mycobacterium avium subsp. paratuberculosis, Escherichia coli), usually during the periparturient period.^218,219 This increased shedding of infectious microorganisms is an important factor in the management of animals through this period. The suppression of neutrophil functions during later stages of pregnancy and immediately postpartum are the subject of active investigation.^215,220

Fig. 53-5 Proposed relationships among shedding of infectious microorganisms during periods of nonpregnant, pregnant, postpartum, and relative immune competence.

Modified from Evermann JF: Immunology of bovine pregnancy: vulnerability to infectious disease, Bovine Proc 26:101, 1994.

The reduced neutrophil function and its association with periparturient immune suppression are significant problems, especially for the transition dairy cow.²¹⁵ This immunosuppression is directly associated with increased postpartum metritis and increased susceptibility to mastitis. As noted with the immunosuppression during pregnancy, this periparturient stage can be aggravated by both preexisting infections (e.g., bovine herpesvirus type 4)²²¹ and environmental bacterial pathogens (e.g., Staphylococcus aureus, Klebsiella species).²²²

Management

Although the immunosuppressive periods during pregnancy and up to 4 weeks postpartum are well recognized, current understanding of the cellular processes is still somewhat rudimentary. However, clinicians and owners can proceed with control measures that accomplish two primary goals: maximize reproductive performance and ensure successful neonatal survival.^210,223,224 Over the years, we have emphasized the importance of effective vaccination programs before breeding, clean birthing areas, and good hygiene for the lactating animal.^210,222 These measures, in conjunction with good colostral management, allow owners to compensate for the temporary immunosuppressive states encountered during and immediately after pregnancy.

Red Blood Cell Antigens

Seven independent RBC groups or systems have been internationally defined in horses under the auspices of the International Society for Animal Genetics^225-228 (Tables 53-3 and 53-4). These systems are named A, C, D, K, P, Q, and U. Additional systems are recognized by individual laboratories. Each system corresponds to a particular gene for which two or more alleles exist. Some blood groups are relatively simple and contain only two alleles, whereas other systems may have over two dozen different alleles.

Table 53-3 Domestic Animal Blood Groups

* Soluble antigens.

From Suzuki: Personal communication, 1990.

Table 53-4 Blood Group Systems, Factors, and Alleles of the Horse Recognized by the International Society for Animal Genetics

* Most common factors involved in neonatal isoerythrolysis (NI).

† Previously reported to cause NI in at least one case.

From Cothran G: Personal communication.

The blood group genes produce surface molecules that contain antigenic sites known as factors. More than 30 different factors have been identified. Each factor is associated with only one system, although the same factor may be associated with more than one allele within the system. The factors are named with an uppercase letter to denote the system and a lowercase letter to designate the factor within that system. Groups of factors that are produced by a single allele are called phenogroups.

The presence of RBC antigens is detected primarily by either agglutination or complement-mediated lysis of test cells by antibodies directed against specific erythrocyte alloantigens. Antigens in some systems are detected with antiglobulin tests.

Eleven blood groups have been identified in cattle²²⁹ (Table 53-5); groups B and J have the greatest clinical relevance. The B group is a very complex system, with more than 60 different antigens.²³⁰ This complexity has been used to advantage for individual animal identification and parentage studies in the past, but it makes it difficult to match donor and recipient blood for transfusions.

Table 53-5 Blood Group Factors of Cattle Recognized by the International Society for Animal Genetics

* Cases of neonatal isoerythrolysis associated with production of anti—red blood cell antibodies against factors in response to anaplasmosis and Babesia vaccines.

† Additional factors are recognized by individual laboratories.

The J antigen is a lipid that is found in body fluid and that is adsorbed to erythrocytes; thus it is not a true erythrocyte antigen. Newborn calves do not have this antigen but usually acquire it during the first 6 months of life. After acquiring it, some groups of cattle have high amounts of J antigen both in the serum and adsorbed to erythrocytes, whereas other groups have very small amounts found only on RBCs. These latter groups, often referred to as J-negative, may actually have anti-J antibodies and develop transfusion reactions when transfused with blood from J-positive donors.²²⁵

Seven blood groups have been identified in sheep (see Table 53-3). The B system is analogous to the B system in cattle and is extremely polymorphic, with more than 52 different alleles. The R system is similar to the J system in cattle in that the antigens are soluble and are passively adsorbed to erythrocytes.²²⁹ The M-L system is involved in the genetically determined RBC potassium polymorphism found in sheep.²³¹

Blood groups of goats appear to be very similar to those of sheep, and many of the reagents used for typing sheep blood have been used to type goats’ blood. Reagents used to detect antigens of the J system of cattle have been used to detect differences in a similar system in goats.²³²

The biologic function of red blood cell antigens is not known for any system in any species with the exception of the M–L blood group system in sheep, which is involved in active potassium transport across red blood cell membranes.

Electrophoretic Markers

Many plasma and intracellular proteins have polymorphic forms. These variants have subtle biochemical differences, which for the most part do not alter the major characteristics of the molecules, but which can be detected using electrophoretic methods. Technically, these are not alloantigens because the differences are not detected immunologically. The various forms of the molecules are detected on the basis of their different rates of migration in electrophoresis. The specific form(s) of any particular protein that an individual possesses are determined genetically, and those used in blood typing are usually expressed co-dominantly. Currently, no diseases are clearly associated with the presence or absence of particular alleles of polymorphic proteins; however, they are useful genetic markers for identification and parentage studies and were typically included in the blood type^227,232-234 (Table 53-6). Electrophoretic markers were used extensively in horses because RBC antigens did not provide the same degree of discrimination among individuals in this species as they do, for example, in cattle. The current application is limited to legacy parentage verification when parental DNA is not available for testing.

Table 53-6 Examples of Polymorphic Proteins Used in Blood Typing

Lymphocyte Antigens

Three systems of equine lymphocyte alloantigens have been described: ELA, ELY 1, and ELY 2.^235-239 ELA is the major histocompatibility complex (MHC) of the horse. ELA is a complex system that includes several genes, each of which is polymorphic (e.g., has many different alleles). Because the MHC regulates the interactions of many cells in the immune response, disease susceptibility or resistance could be associated with ELA. An association between a particular ELA allele and equine sarcoid has been described.^240,241 ELY 1 and ELY 2 have limited polymorphism and appear to be two allele systems.

The MHC of cattle is called BoLA, for bovine lymphocyte antigen. In sheep the MHC is called OLA, for ovine lymphocyte antigen, and is also known as SH-LA. In goats the comparable system is GLA.²⁴²

Equine

Definition and Etiology

Neonatal isoerythrolysis (NI) is a condition characterized by the destruction of RBCs in the circulation of a foal by alloantibodies of maternal origin absorbed from colostrum.^226,248,249

Production of alloantibodies can be stimulated in mares several ways, including transfusion, exposure to blood from the foal during parturition, or as a result of placental pathology during gestation. Incompatibilities of at least some blood groups between the dam and foal are the rule rather than the exception, and yet the incidence of sensitization of the dam and occurrence of NI is relatively low. In thoroughbreds the prevalence is about 1% and in standardbreds about 2%.²⁵⁰ The prevalence in mules (donkey sire, horse dam) has been reported to be as high as 10%.²²⁶ Most blood groups are not strongly antigenic under the conditions of exposure through previous parturition or placental leakage. Several blood group factors, however, are particularly immunogenic, and antibodies against these antigens have been reported to cause almost all cases of NI. These include factor Aa in the A system and factor Qa in the Q system. In mules a unique donkey RBC antigen named donkey factor has been associated with NI.²⁵¹ Antibodies to these antigens develop after the exposure of the mare to RBCs and are not naturally occurring antibodies. In humans the absence of certain RBC antigens results in the production of natural antibodies against that antigen, presumably because of exposure to cross-reacting antigens in the diet. This does not occur in horses (with a few exceptions) and has not been associated with NI. Ca-negative (Ca−) horses frequently make anti-Ca antibody of low titer without known RBC exposure. However, anti-Ca antibody is generally not associated with NI, and mares with anti-Ca antibody actually appear less likely to develop certain antibodies responsible for NI.

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For NI to occur, several conditions must be present (Figs. 53-7 and 53-8). First, the dam must be negative for the antigen in question. Because most cases of NI in horses are associated with either anti-Aa or anti-Qa antibodies, mares that are Aa− or Qa− or both are considered at risk. All horses appear to lack donkey factor; thus all mule pregnancies are considered at risk. Second, the mare must become sensitized and produce antibody to the offending antigen. Sensitization can result from exposure during a previous pregnancy, blood transfusion, or transplacental contamination with fetal RBCs earlier in the current pregnancy (rare). Third, the foal from the current pregnancy must have inherited from its sire the antigen(s) to which the mare has been sensitized. When these conditions are met, there is a significant potential that maternal antibody directed against the foal’s RBC antigens will appear in the colostrum and, if subsequently ingested and absorbed by the foal, could cause loss of RBCs. The higher the anti-RBC titer is at foaling, the higher the risk. The highest titers are likely to be produced in a previously sensitized mare that is reexposed to the same RBC antigens shortly before parturition.

Fig. 53-7 Entrance of RBCs of paternal antigen type into maternal circulation stimulates the production of alloantibody in the mare’s serum.

Fig. 53-8 Alloantibody in the mare’s serum is concentrated in colostrum at the end of gestation. Through passive transfer, the foal absorbs immunoglobulins, including these alloantibodies. The antibodies attach to RBCs and cause either their premature removal from circulation or intravascular lysis.

Ruminants

Neonatal isoerythrolysis is not a naturally occurring disease in cattle, sheep, or goats. Its occurrence in cattle has been associated with administration of vaccines derived from blood, such as certain anaplasmosis and babesiosis vaccines.²²⁶ When used on breeding females, these vaccines may sensitize the dam to certain blood groups, most often in the A and F systems. Under chance circumstances, if the blood types of the sire and offspring reflect these systems and the dam has produced alloantibodies, an isoimmune hemolytic crisis may appear in the calf associated with successful passive transfer. Hemolytic crises are rare in sheep and are even difficult to induce experimentally.²²⁶

Definition and Etiology

Neonatal alloimmune thrombocytopenia (NAIT) is a condition characterized by the destruction of platelets in the circulation of a foal by alloantibodies of maternal origin absorbed from colostrum.²⁶⁴ The syndrome has been observed in horse and mule foals.^251,264,265 The prevalence of NAIT is not known. Some foals may be asymptomatic, and the condition may be self-limiting as alloantibody is metabolized.

Clinical Signs and Differential Diagnoses

Few clinical signs may appear unless foals are traumatized. Affected foals may have prolonged bleeding from venipuncture sites. Petechial hemorrhages may not be present. Other conditions often associated with thrombocytopenia in neonates include sepsis, disseminated intravascular coagulation, equine infectious anemia, drug-induced thrombocytopenias, and angiopathies. The challenge is to determine whether the thrombocytopenia is primarily caused by allogeneic antibodies or secondary to some other disease process. For differential diagnoses of thrombocytopenia in neonatal foals, see Chapter 19.

Clinical Pathology

Profound thrombocytopenia in the absence of other hematologic changes typifies uncomplicated NAIT. Evidence of successful passive transfer is present based on quantification of serum IgG. Affected foals are thrombocytopenic. Thrombocyte counts less than 10,000/μL have been observed. Prolonged bleeding from venipuncture sites and petechiae may be present.²⁶⁴ Demonstration of significant amounts of antibody in the colostrum (or serum from the mare) that are directed against platelet antigens expressed by the foal provides a definitive diagnosis of NAIT. However, assays for equine platelet-bindable and platelet-associated immunoglobulins are not routinely available.

Pathophysiology

The pathophysiology is believed to mirror that of neonatal isoerythrolysis. In mares sensitized to platelet antigens, alloantibodies are concentrated in the colostrum late in gestation. These antibodies are passed to the foal through passive transfer. If the foal’s platelets carry the antigen that the antibody recognizes, the platelets become antibody coated. Subsequently, they are removed prematurely by the reticuloendothelial system. Platelet antigens have not been characterized in horses; however, platelet-associated antibodies have been demonstrated in affected foals. Circulating antibody is removed by attachment to platelets and rapid clearance by the reticuloendothelial system.

Treatment and Prognosis

Circulating antibody is removed relatively quickly, and treatment may not be necessary. Platelet-rich plasma may be indicated in cases of serve thrombocytopenia accompanied by clinical signs of bleeding problems. As offending antibody is removed, however, the problem will tend to be self-limiting.

Prevention and Control

Currently, there are no screening tests to predict NAIT. After production of an affected foal by a mare, it would be prudent to provide an alternate source of colostrum to foals born in subsequent pregnancies.