Diseases of the Immune System

Thymoma

Neoplasia is comparatively uncommon in goats, but thy­moma is one of the two most commonly recognized caprine tumors. It occurs more frequently in goats than in other domestic species.

Epidemiology

Thymoma is rarely seen in goats younger than 2 years of age. There is no sex predilection. Because thymomas rarely produce clinical disease, recognition of thymoma in goats has come mostly from slaughterhouse surveys and as an incidental finding in necropsy studies. At one veterinary diagnostic laboratory in the United States, 102 tumors were diagnosed in goats over a 25-year period and 9 of them were thymomas occurring in goats from 2 to 12 years of age (Lohr 2012). The highest prevalence has been reported in a group of Saanen goats used for slow virus research studies; 17 of 92 goats (18.5%) had thymomas at necropsy, with a prevalence of 25.3% in goats older than 2 years of age (Hadlow 1978). Slaughterhouse surveys indicate a lesser prevalence in general goat populations, with 8 cases per 100 000 goats in one study and 14 of 2600 adult Angora goats in another, but this is still more than the prevalence of thymoma in other livestock species (Streett et al. 1968; Migaki 1969).

Clinical Findings

Most occurrences of thymoma are subclinical, but occa­sionally thymomas have been associated with clinical disease. Congestive heart failure secondary to thymoma was recorded in two aged Nubian goats (Rostkowski et al. 1985). These cases are discussed in more detail in Chapter 8. There is also a case of megaesophagus in an 8-year-old Saanen doe secondary to a thymoma and an associated hematoma, which put pressure on the tho - racic esophagus. The goat presented with a history of recurrent tympany and regurgitation after eating (Parish et al.

A review of 13 clinical cases of thymoma in goats has been published (Hill et al. 2017). In some of the cases, the thymoma was present as a visible or palpable mass in the ventral cervical region and the presence of the mass was the reason for seeking veterinary attention. In others, the tumors were present in the mediastinum and were later identified by diagnostic imaging. The goats with mediasti­nal thymomas presented with a history of respiratory signs, including tachypnea or respiratory distress and, in some cases, muffled lung and heart sounds, coughing, lethargy, and/or weight loss.

Clinical Pathology and Necropsy

The majority of thymomas occur in the cranial mediastinal cavity and occasionally at the thoracic inlet, but they also can occur in the ventral cervical region. Tumor size is variable, with some weighing up to 600 g. The tumors are encapsulated, firm, and grayish white, and the larger ones tend to be lobulated. On cut surfaces they can contain areas of hemorrhage, cysts, and focal yellow areas of necrosis, sometimes associated with calcification. Metastases are rare, but adhesions to adjacent structures, especially lungs, do occur. In one report, pulmonary metastases from a thy­moma were identified in an 8-year-old castrated male French Alpine goat with a history of progressive weight loss, exercise intolerance, and anorexia (Olchowy et al. 1996).

Diagnosis

Lymphosarcoma involving the thymus occurs rarely in goats and must be differentiated from thymoma. In thy­moma, the principal neoplastic cell is a polymorphic epi­thelial cell that is often spindle shaped, but can be round or ovoid. Lymphocytes are present in thymomas and may predominate, but they do not exhibit characteristics of neoplastic transformation. The neoplastic cell in lympho­sarcoma is the lymphocyte. Because it often produces peripheral lymphadenopathy, lymphosarcoma is dis­cussed in more detail in Chapter 3. Normal thymic tissue is commonly found near the thyroids and at the base of the neck in healthy goat kids, but thymomas have not been seen in goats under 2 years of age.

Treatment and Control

The surgical removal of thymomas in goats has been reported, as well as one instance of treatment with external beam radiation (Hill et al. 2017). Outcomes were favorable for excision of thymomas located in the ventral cervical region, but the procedure was more problematic for thymo­mas located mediastinally. The reported high incidence of thymoma in Saanen goats used in slow virus research sug­gests that either genetic or viral factors may play a role in the development of caprine thymoma. This merits addi­tional investigation, particularly because the retroviral dis­ease CAE is widespread in goats.

Failure of Transfer of Passive Immunity

Newborn goats, like the young of other livestock species, depend on the ingestion of antibody-rich colostrum shortly after birth to provide passive immunologic protec­tion until they can actively produce their own array of protective antibodies. The failure to absorb adequate anti­bodies in the immediate postpartum period predisposes young goats to serious infectious disease problems and high mortality rates.

Epidemiology

Unacceptably high levels of death loss in young goats are recognized as a major constraint on goat production wher­ever goats are raised. The factors contributing to kid death in various goat-producing regions of the world have been reviewed (Sherman 1987; Morand-Fehr 1987). In extensive management systems, kid losses have been reported in the range of 10-60% and, in intensive management systems, from 8 to 17%. These deaths most frequently occur in the first few days of life. Numerous factors contribute to this bias toward early death, including low birthweight, prema­ture delivery, large litter size, poor mothering ability, and environmental and weather conditions at the time of kid­ding. However, the failure to suckle adequate colostrum at birth contributes significantly to the preponderance of early kid deaths, most likely through the mechanism of failure of transfer of passive humoral immunity, as dis­cussed below under pathogenesis.

In addition to providing immunity against infectious dis­ease and reducing neonatal mortality, there are indications that consumption of adequate colostrum by the neonate is associated with other long-term benefits. There are positive correlations between serum IgG concentration at 24 hours of age (sIgG-24) and weaning weight in beef calves, as well as positive correlations with first lactation milk production and milk fat content in dairy heifers. In goats, a significant correlation is reported between sIgG-24 and average daily weight gain in pre-weaned dairy goat kids measured up to 30 days of age (Massimini et al. 2007).

Etiology and Pathogenesis

The syndesmochorial (epitheliochorial) placentation of the goat does not permit the transfer of Ig from the mater­nal circulation to the fetus during gestation. Therefore, the kid is born in an agammaglobulinemic state and, though immunocompetent, is highly susceptible to infection because of the immediate lack of circulating humoral anti­body. Passive immunization of the newborn kid depends on early oral ingestion of colostrum containing maternally produced Ig. The doe experiences an increase in antibody production, notably of the IgG₁ class, in the weeks preced­ing parturition, and IgG₁ antibodies are preferentially transported into the colostrum, aided by the affinity of the Fc fragment of IgG₁ for receptors on mammary epithelial cells. The mean concentrations for IgG₁ and IgG₂ in doe serum are reported as 10.9 and 9.1 mg/mL, respectively, while in colostrum the relative mean concentrations are 50.8 mg/mL for IgG₁ and 2.3 mg/mL for IgG₂ (Micusan and Borduas 1977).

The newborn kid, upon ingesting colostrum, is capable of transporting intact Ig molecules out of the intestinal lumen and into the blood circulation. Survival of intact antibody molecules in the gut lumen probably depends on the pres­ence of trypsin inhibitors present in colostrum. The mecha­nism of transintestinal transport is pinocytosis through the original neonatal intestinal epithelial cells. It is presumed that as these cells are sloughed and replaced in the normal process by new epithelial cells, the capacity for additional pinocytosis and additional intestinal absorption of Ig is lost. In the calf and lamb, maximal absorptive capacity is believed to persist for six hours after birth, with all absorptive capac­ity absent by 24 hours of age, although this is conditioned to some extent by extrinsic factors such as the time of first suckling. In contrast, the kid may be able to effectively absorb antibody for a longer period, perhaps as long as four days. In one study, kids fed milk only at birth and not given colostrum until 72 hours old demonstrated increased serum antibody levels after colostrum administration. The level achieved, however, was not as much as that observed in kids receiving colostrum at birth, and mortality rates were higher (Vihan and Sahni 1982). Therefore, the potentially longer period for intestinal absorption of colostral antibodies in kids is no reason for delaying the ingestion of colostrum. The fact that the concentration of antibody in colostrum decreases rapidly after the first 6-12hours also underscores the importance of early ingestion.

A number of factors influence the ultimate level of Ig reaching the serum of the kid and the immunity derived from it. Most of these considerations have been elucidated specifically for the lamb, but are also considered to be applicable to the kid (Levieux 1984). These include the ability of the kid to suckle early after birth, volume of colostrum available, absorptive potential of the kid, con­centration of antibody in the colostrum, and diversity and activity of the antibody.

The ability of kids to absorb Ig after ingestion of colos­trum depends primarily on the time of colostrum inges­tion, with earlier ingestion promoting better absorption. Birthweight and length of gestation are reported to be negatively correlated with absorption of Ig. However, there are apparently other unknown factors that affect the intrin­sic ability of individual kids to absorb Ig. When newborn kids were administered colostrum from a common source on a per weight basis at the same time interval after birth, serum antibody levels subsequently varied by as much as a factor of eight. In addition to kid factors, maternal factors affect absorption. The concentration and character of Ig in does can also vary. Older does are likely to have a wider immunologic experience than young does and provide a more diverse spectrum of protective antibodies to kids. Breed variation has been observed in both ewes and does (Nandakumar and Rajagopalaraja 1983b; Levieux 1984). In the dairy breeds, where colostrum is produced well in excess of that required by offspring, IgG concentrations in the colostrum and subsequently in the kids' serum can be present in levels considerably higher than those reported for non-dairy breeds.

The majority of ingested antibody, primarily IgG₁, is absorbed across the intestinal tract to become circulating humoral antibody. Therefore, the key protective role of colostral antibody is prevention of general infection, and the most common cause of death in colostrum-deprived kids is colisepticemia. Doe colostrum also contains small amounts of IgA and IgM, 1.7 mg/mL and 3.8 mg/mL, respectively, but the role of colostral antibody in protecting against local mucosal infection, particularly in the gut, is rather limited.

While absorbed antibody is clearly beneficial to the kid in terms of immediate disease protection, passive antibody can have a retarding effect on the development of the kid's own active immunity. Experimental evidence demon­strates that in colostrum-deprived kids circulating IgG₂ appears earlier in the serum than in colostrum-fed kids, and that by 12 weeks of age circulating levels of both IgG₁ and IgG₂ are higher in colostrum-deprived kids than in colostrum-fed kids (Micusan et al. 1976).

Based on studies of the disappearance of antibodies spe­cific for Co. pseudotuberculosis from kid serum after colos­trum ingestion, the half-life of passively acquired antibody is approximately 12 days, with some antibody still detecta­ble in most kids between 5 and 6 weeks of age (Lund et al. 1982). Persistent antibodies may inhibit active immu­nization with homologous vaccines. When colostrum-fed kids were immunized with human gamma globulin, a pro­tein with which their dams had been previously immu­nized, they showed no measurable antibody response to immunizations at birth and 4 weeks of age, and responded only at 8 weeks of age when passive antibody levels to the protein had diminished (Micusan et al. 1976). These obser­vations are of practical concern when planning vaccination schedules for young goats.

Clinical Findings

There are no specific clinical signs of FTPI per se. The con­dition is suggested by kid deaths occurring within 48 hours of birth, in association with clinical signs of septicemia. These include acute collapse, very high or subnormal body temperature, cold extremities, congested mucous mem­branes, rapid heart rate and thready pulses, and dehydra­tion. Evidence of navel infection, diarrhea, or swollen joints may also be suggestive of septicemia, but many kids die before these signs are observable. Hyperesthesia, sei­zure activity, or ophistotonos may be observed because of bacterial invasion of the central nervous system or con­comitant acidosis. Pneumonia, enteritis, or a pneumoen­teritis complex occurring in kids during the first few weeks of life is also suggestive of FTPI.

A careful history should be taken to determine if the affected kids were observed to suckle, the time of suckling, whether the caretaker provided colostrum by bottle, and whether navels were disinfected after birth. Examination of the kidding and housing areas for evidence of poor sani­tation and lapses in good management technique may sug­gest that septicemia secondary to FTPI is involved.

Clinical Pathology and Necropsy

The most direct method for determining if FTPI is involved in death losses is to measure circulating Ig levels in the serum or plasma of kids. The optimal time for obtaining serum samples from kids is between 24 and 48 hours of life, because maximum antibody absorption from the gut will have occurred during that time. Methods reported specifi­cally for direct or indirect determination of serum Ig in kids are limited compared with other livestock species.

Documented tests for goats include a quantitative zinc sul­fate turbidity test and a qualitative glutaraldehyde coagula­tion test (Vihan 1989; Sherman et al. 1990). Using the zinc sulfate turbidity test, kids receiving 480mL of heat-treated goat colostrum in the first 24hours of life had mean Ig levels of 1.5 g/dL when tested 24 hours after the last colostrum feeding. Using the glutaraldehyde coagulation test, serum from kids with Ig levels less than 1g/dL did not clot after 60 minutes' incubation with 10% glutaraldehyde solution.

The use of total protein determination by optical refrac­tometry and a sodium sulfite precipitation test has been described for deriving reliable, indirect estimates of Ig levels in kids under field conditions (O'Brien and Sherman 1993a). When FTPI was defined as a serum IgG < 1200 mg/dL, all cases of FTPI were indirectly identi­fied using total protein determination by refractometry when the cutoff for total protein was set at 5.4 g/dL. The use of Brix refractometry on kid serum samples also has been reported, with Brix% values less than 8.6% on day 1 post suckling and 9.2% on day 2 post suckling as indicative of FTPI (Batmaz et al. 2019). Direct measurement of IgG in goat serum can be done using radial immunodiffusion (Massimini et al. 2007) and ELISA.

Studies correlating antibody level to morbidity and mor­tality in kids are scarce compared with similar work for calves, lambs, and foals, so minimal acceptable levels of circulating Ig for kids under different systems and condi­tions of management are not established. In a prospective study of kid survival in relation to circulating Ig levels in intensively managed dairy goat kids in New England, in the United States, a serum Ig level of 1200 mg/dL appeared to be protective (O'Brien and Sherman 1993b). A study conducted under extensive management conditions indi­cated that serum Ig levels of 800 mg/dL were protective in goat kids (Mellado et al. 1998).

An indirect method for evaluating Ig absorption by measurement of serum gamma glutamyl transferase (GGT) levels in kid serum has been reported. The mean serum GGT levels in pre-suckling newborn kids was 19 U/L, with a maximum recorded measurement of 28 U/L. At 24 hours after colostrum ingestion, serum GGT levels were on aver­age six and a half times greater than pre-suckle levels, with a mean of 127 U/L and a minimum reported value of 43 U/L. The mean GGT level fell rapidly after 24 hours, so timing appeared critical in the evaluation of the test results (Braun et al. 1984).

Goats with septicemia secondary to FTPI are likely to be severely leukopenic and may show hyperfibrinogenemia. Necropsy results are non-specific, but bacterial culture results of heart blood and various other organs can estab­lish the presence of septicemia.

Diagnosis

Low serum Ig levels in newborn kids 24 hours of age or older confirms the presence of FTPI. The contribution of this condition to concurrent disease problems can only be inferred. In kids dead before 24 hours, FTPI may be contributory, but this is more difficult to establish. Hypothermia and hypoglycemia must always be consid­ered in the differential diagnosis of septicemia secondary to FTPI. Hypoglycemia may be presumed in the live ani­mal by measurement of blood glucose, although blood glucose is also likely to be decreased in active septicemia. The absence of an inflammatory hemogram supports pri­mary hypoglycemia, as does the absence of a milk clot in the abomasum or ingesta in the small intestine, indicat­ing lack of feed intake. A diagnosis of hypothermia is supported by low body temperature in conjunction with environmental conditions that would promote chilling, such as outdoor kidding, cold temperatures, wet weather, and drafts. In individual kids, congenital abnormalities must also be considered as a cause of early death. Under conditions of extremely poor management and with suf­ficiently virulent organisms, septicemias can occur even when adequate colostrum has been ingested shortly after birth.

Treatment

In most cases, FTPI first comes to the veterinarian's atten­tion because of a primary complaint of early deaths or signs of shock suggesting the presence of septicemia. Immediate attention must be given to the management of the infection. Animals should be moved to a warm, dry environment. IV fluid therapy including glucose and sodium bicarbonate should be initiated to counter the hypoglycemia and circu­latory effects associated with septic shock. Parenteral non­steroidal anti-inflammatory drugs such as flunixin meglumine may be helpful. Antibiotic therapy is essential. Choice of drugs ideally should depend on blood culture, but therapy should be initiated immediately with broad­spectrum antibiotics, especially those with efficacy against Gram-negative species. Trimethoprim-sulfa combinations or gentamicin combined with ampicillin can be effective. Aminoglycoside drugs must be used cautiously to avoid serious renal damage, particularly if fluid therapy is not used concurrently. Note that the use of gentamicin in goats in the United States is extralabel, and in cattle the meat withdrawal time is 18 months. Chloramphenicol, where permitted, is also effective in septicemia. Its use in goats is expressly forbidden in the United States.

Correction of the hypogammaglobulinemia requires transfusion of plasma or whole blood. The volume required to replace the Ig deficit depends on the known level of cir­culating Ig in the sick kid and the average or known level of Ig in the blood of the donor goat. The average circulating serum Ig level of does is approximately 20 mg/mL. Although the minimum level of acceptable circulating immunoglob­ulin required by the kid has not been established, in most cases an initial transfusion of at least 250 mL of plasma is required for an average-sized kid. Repeated evaluation of zinc sulfate turbidity test results after plasma administra­tion can aid in determining the need for additional transfusions.

Prevention

All goat caretakers should be aware of the potential economic losses associated with FTPI to newborn kids through colos­trum and educated on aspects of neonatal management related to colostrum administration. Careful observation of goats at kidding time may be necessary to identify individual kids that do not effectively suckle by 6 hours of age. These kids should be bottle fed or tubed with colostrum at a rate of 50 mL of colostrum per kg bw for each of four feedings over the first 24 hours of life. In intensive management systems, caretakers responsible for kid rearing can be encouraged to electively administer colostrum to all kids routinely within six hours of birth, rather than wait for it Iooccurrnilurally.

The maintenance of a frozen colostrum bank ensures that all kids have colostrum available regardless of the sta­tus of their dams. In preparing frozen colostrum, only that taken from does during the first 12 hours after kidding should be kept for freezing, because the concentration of Ig in colostrum falls off rapidly and dramatically after the first stripping. It is reported that Ig concentration of caprine colostrum shows a strong positive correlation to its specific gravity, so that colostrum quality can be screened using a colostrometer, a hydrometer that uses the correlation between colostrum density and IgG concentration to give us a measure of colostrum quality. Brix refractometers, designed to assess sugar content in aqueous solutions and used widely in the food and beverage industry, have also been validated for assessing colostrum quality in goats and are suitable for use on the farm (Zobel et al. 2020).

Colostrum with a specific gravity more than 1.029 is pre­ferred (Ubertalle et al. 1987). The IgG concentration of fro­zen goat colostrum was not affected by the method of thawing, be it in hot water (60 °C), by refrigeration (4 °C), at room temperature (27 °C), or in a microwave (55 °C) (Arguello et al. 2003). As an alternative to freezing, colos­trum can also be lyophilized and stored for later use to pro­vide satisfactory uptake of Ig (Castro et al. 2005).

Bovine colostrum, either fresh or frozen, has been used successfully as a substitute for ewe colostrum in rearing lambs. This has also gained popularity in goat-rearing in an attempt to limit the colostral transmission of CAE virus in kids. Serum Ig levels achieved in kids suckling bovine colos­trum are equivalent to those obtained with caprine colos­trum (Sherman et al. 1990). However, this practice has been associated with a potential risk. In France, a hemolytic syn­drome has been reported in some kids at 1 week of age after consumption of bovine colostrum. It was demonstrated in vitro that bovine antibodies were directed against some caprine erythrocytes (Perrin et al. 1988). Furthermore, con­taminated bovine colostrum could introduce diseases to which goats are susceptible, e.g., paratuberculosis.

Concerns have arisen regarding the impact of heat treat­ment techniques on immunoglobulin content of goat colostrum used in CAE control programs. The original heat treatment protocol of 56 °C (132.8 °F) for 60 minutes was developed to avoid the denaturing effect on antibody asso­ciated with the higher temperatures of pasteurization, while still inactivating the CAE virus (Adams et al. 1983). However, other studies demonstrate in vitro that heat treat­ment of colostrum at 56 °C for 60 minutes can reduce measurable IgG in colostrum by up to 37% (Arguello et al. 2003). Nevertheless, if the initial concentrations of the colostrum that is heat treated are sufficiently high, suc­cessful transfer of maternal antibody may still be achieved. A later study indicated that heat treatment at 56 °C for 60 minutes or at 63 °C for 30 minutes had equivalent effects, reducing the IgG content of colostrum by only 15% (Trujillo et al. 2007).

A number of commercial products are available that have been promoted as colostrum supplements for calves, lambs, and kids, but have been used by goat owners as colostrum substitutes, in part to avoid the need for heat treating colostrum for CAE control, which can be cum­bersome and time-consuming. These products are usu­ally in the form of soluble powders or boluses. It should be noted that product quality can vary considerably. In one study, two of these products were evaluated in kids. There was virtually no detectable increase in circulating serum Ig levels in colostrum-deprived kids receiving these oral products within 12 hours of birth (Sherman et al. 1990). Other reports have corroborated the inade­quacy of certain colostrum substitutes in achieving ade - quate Ig levels in kids receiving the products (Constant et al. 1994).

Commercial colostrum substitutes of bovine origin are now marketed for goat kids and lambs in the United States that are tested and licensed by the US Department of Agriculture to confirm the levels of Ig present. Some of these products are also batch tested by the manufacturer to confirm that they are free of Mycobacterium avium subsp. paratuberculosis. Hemolytic anemia has not been reported with these products.