Failure of passive transfer (FPT) in neonatal foals is the most common immunodeficiency disorder in the horse, occurring in between 3–24% of newborn foals (Sellon, 2000; Giguère and Polkes, 2005). It is defined as the failure of the foal to ingest or absorb adequate immunoglobulin from colostrum, and is associated with an increased risk of infectious disease and mortality (McGuire et al, 1975; Sellon, 2000). Therefore detection and treatment of failure of passive transfer is important in reducing morbidity and mortality in neonatal foals.
Passive transfer of immunity
Although a large proportion of immune system development occurs during gestation, the foal is considered immunologically naive at birth. Both IgM and IgG proteins are evident in fetal serum prior to 200 days gestation (Perryman and McGuire, 1980) and the fetus is capable of generating antigen-specific immune responses (Tallmadge, 2016). However, in utero the fetus is protected from exposure to pathogens, and it is rare for a primary immune response to occur prior to birth. Therefore, although the newborn foal is considered immunocompetent, meaning that it can initiate an immune response, it is immunologically naive as it has not yet been exposed to pathogens and developed the appropriate antigen-specific responses (Mealey and Long, 2018). In addition, the epitheliochorial structure of the equine placenta means that maternal immunoglobulins are unable to pass to the foal via the placenta and foals are essentially born agammaglobulinaemic. As a consequence, foals lack immediate immune protection following birth, and the ingestion and absorption of immunoglobulins in colostrum from the dam (Figure 1) is therefore critical (Giguère and Polkes, 2005). This passive immunity provides the foal with protection at birth, and should be sufficient to cover the foal for up to the first 3 months of life, at which point endogenous antibody production should reach protective levels.
Colostrum is a specialised form of milk containing concentrated immunoglobulins. It is produced during the last 2–4 weeks of gestation. under hormonal influence, and is only produced once for each pregnancy. It is then replaced, within 24 hours of the initiation of lactation, by milk containing negligible quantities of immunoglobulins (Jeff cott, 1974). Colostrum contains primarily IgG, with lesser amounts of IgA and IgM, all of which have been concentrated into mammary secretions from the mare's blood (Perkins and Wagner, 2015). In addition to immunoglobulins, colostrum also contains other factors such as complement components, cytokines, lysozyme and ferritin, that are likely to play significant roles in neonatal immune induction and development and protection against pathogens.
The ability of the foal to absorb immunoglobulins is greatest during the first 6 hours aft er birth, then steadily declines until immunoglobulins can no longer be absorbed when the foal is approximately 24 hours old (Jeff cott, 1971). Absorption is non-specific, and is the result of pinocytosis by specialised enterocytes in the small intestine (Cervenak and Kacskovics, 2009). Gut ‘closure’ is likely to result from the replacement of these specialised enterocytes with more mature cells (Perkins and Wagner, 2015).
Failure of passive transfer
Failure of the foal to ingest or absorb sufficient quantities of immunoglobulins is described as FPT and is the most important risk factor for the development of infection and death in the first month of life (Sellon, 2000). A foal is considered to have FPT if circulating IgG concentrations are <400 mg/dL at 24 hours of age. Partial FPT is defined as 400–800 mg/dL, while a blood concentration of >800 mg/dL is considered adequate transfer of immunoglobulins. A negative correlation between foal IgG concentration and the incidence of severe infections has been demonstrated (McGuire et al, 1977). A serum IgG concentration of greater than 800 mg/dL is associ-ated with a significantly higher rate of survival, and is therefore considered an appropriate threshold (Giguère and Polkes, 2005; Sellon, 2000). Tyler-McGowan et al (1997) reported that foals with partial failure of passive transfer also had increased susceptibility to severe disease. However, the actual concentration of IgG required for protection of a foal from infection will depend on additional factors such as the virulence and load of environmental pathogens; the colostral antibody titres against specific pathogens; and the presence of additional stress factors. Therefore, serum concentrations between 400–800 mg/dL may be considered adequate in healthy, low-risk foals on well-managed farms.
The causes of FPT in foals are:
- Failure of the foal to ingest sufficient colostrum in the early postpartum period
- Insufficient absorption via the foal's small intestine
- Loss of colostrum before par-turition via premature lactation;
- Failure of the mare to produce adequate quantities of good-quality colostrum.
A foal may fail to ingest adequate sufficient colostrum in the early postpartum period if it is separated from or rejected by the dam, or if the foal has systemic, orthopaedic or neurologic abnormalities that prevent it from being able to stand and nurse. If the ingestion of colostrum is delayed beyond 6 hours of birth, then the absorption of immunoglobulins is dramatically reduced. Foals that have ingested adequate quantities of good-quality colostrum may still develop FPT if there is malabsorption of immunoglobulins via the small intestine. This is often observed in premature or dysmature foals or in foals with concurrent disease. A proposed cause of reduced immunoglobulin absorption in such cases is stress causing endogenous glucocorticoid release, which hastens the maturation of specialised enterocytes.
Maternal causes of FPT include loss of colostrum or failure to produce sufficient concentration or volume of colostrum. Because colostrum is produced only once for each pregnancy, foals from mares with premature lactation are likely to suffer from FPT. Premature lactation is most commonly associated with placentitis, twin pregnancies and premature placental separation, but can occur without concurrent pathology. There is wide variation in colostral concentrations, and poor quality colostrum (IgG concentration <3000 mg/dL) is a risk factor for the development of FPT (Morris et al, 1985). A Brix refractometer can be used as a convenient stall-side method to accurately estimate colostral IgG content, with >20% indicating adequate-quality colostrum.
Diagnosis of FPT
Findings from the patient's history may be useful in order to anticipate failure of passive transfer (eg. premature lactation, failure of the foal to nurse), and abnormalities on clinical examination can help to identify any concurrent disease process. However, FPT alone is not associated with any recognisable clinical signs. The diagnosis of FPT is made based on the foal's serum IgG concentration: as stated above, serum IgG concentrations of <400 mg/dL at 24 hours old is indicative of complete FPT and concentrations between 400–800 mg/dL are considered as partial FPT.
Due to the increased risk of infection associated with FPT, early diagnosis is crucial to the foal's health. Routine screening of foals within the first 24 hours of birthis therefore recommended. Generally, IgG concentration is measured at 18–24 hours of age, at which time serum IgG concentration has reached its peak. Neonates at high risk of FPT, or with evidence of sepsis, may be tested as early as 6–12 hours after birth, as this may give an early indication of FPT and allow prompt intervention.
Single radial immunodiffusion (RID) is the most quantitatively accurate test available for determining serum IgG, and is considered the gold standard for the diagnosis of FPT (Clabough et al, 1989; Sellon, 2000). However, disadvantages of this test include the cost, technical skills and time required to perform the test, making this test impractical for routine screening for FPT.
A variety of screening tests are available that can estimate the concentration of IgG and provide rapid, stall-side results, allowing convenient and timely detection of FPT in foals. Failure to diagnose and treat FPT could have significant consequences in terms of the foal's mortality, therefore for the purposes of screening a sensitive test is required. A high sensitivity ensures a high predictive value of a negative test, therefore allowing the highest proportion of foals with FPT to be identified. However, unnecessary treatment is also undesirable (due to the cost of treatment and the potential for adverse side effects), therefore a positive result should then be confirmed using a more specific test.
Rapid tests used for routine diagnosis of FPT include gluteraldehyde coagulation, zinc sulphate turbidity and ELISA-based tests, such as the Snap Foal IgG test (IDEXX). The SNAP test is convenient, demonstrates good performance, and is semiquantitative, making it a popular first choice. A quantitative point-of-care turbidimetric immunoassay has been evaluated; this showed reasonable performance when assay-specific cutoffs were used, offering a suitable alternative for the stall-side diagnosis of FPT (Ujvari et al, 2017).
Quantitation of total serum protein by refractometer is technically simple and cheap to perform; however, this has been shown to be relatively inaccurate as an indicator of serum IgG concentrations in foals (Rumbaugh et al, 1978). A recent study by Elsohaby et al (2019) investigated the use of digital and optical refractometers for the detection of FPT in foals. These techniques were found to have potential as rapid, inexpensive methods for screening foals. However, the cut-off values used for optimal sensitivity resulted in a lower test specificity, requiring a more specific test to be used to confirm FPT positive foals. Additionally, the number of diseased foals in the study was small and further studies are warranted to validate the usefulness of these refractometers in a larger number of sick foals.
It is also important to consider the population in which the test will be used, as the sensitivity and specificity of a diagnostic test may differ in healthy and sick animals. For example, Metzger et al (2006) reported that the SNAP Foal IgG test has good sensitivity but moderate to poor specificity for the detection of FPT in hospitalised foals.
Management of FPT
Management of FPT depends on several factors including the age of the foal at the time of diagnosis and the presence of concurrent disease, such as sepsis. Ensuring the ingestion of adequate high-quality colostrum is paramount in FPT prevention. Foals that have not nursed within 3 hours of foaling should be administered colostrum by nasogastric intubation. Similarly, foals that are at increased risk of FPT because of premature lactation or poor quality of colostrum should be administered an alternative source of colostrum either orally or by nasogastric intubation. Ideally this should be good-quality colostrum from a donor mare. It is important to note that oral administration by bottle feeding should only be performed in foals with a strong suck reflex. A minimum of 2 L of equine colostrum should be administered in 500 mL doses during the first 6–8 hours following birth (Mealey and Long, 2018). Commercial colostrum substitutes are available, however these will not necessarily provide pathogen specific immunity. It has also been suggested that such substitutes may increase the risk of adverse immunologic reactions if a subsequent plasma transfusion is needed.
Foals that are 12–18 hours old at the time of diagnosis will have a significantly reduced ability to absorb immunoglobulins via the small intestine and should therefore receive an intravenous plasma transfusion. The volume of plasma required to increase the serum IgG concentration to an acceptable level is dependent on the severity of the FPT, the immunoglobulin content of the plasma, and the presence of concurrent disease, which can hasten immunoglobulin catabolism (Wilkins et al, 1994). Typically, an increased of 200–300 mg/dL will be achieved for each litre of plasma given to a 50 kg foal (Tilley et al, 2001). The IgG concentration should be re-assessed following plasma transfusion, to ensure an adequate concentration has been reached. If an adequate concentration has not been obtained then further plasma should be administered.
Clinically normal foals with partial FPT may not require a plasma transfusion if they are on well-managed farms and not considered to be at increased risk of infectious disease. These foals should be monitored closely for the development of infections. However, it is generally recommended for foals at risk of developing sepsis, with partial FPT, to be administered plasma (Sellon, 2000).
Conclusions
Ensuring passive transfer of immunity is critical to the health of the neonatal foal and is fundamental to reducing the risk of infection and mortality. Routine screening of all foals should be performed, in order to ensure that adequate transfer of immunoglobulins has occurred and to allow prompt treatment of failure of passive transfer.
KEY POINTS
- Foals are immunologically naive at birth and obtain passive immunity by the ingestion and absorption of immunoglobulins from the dam's colostrum.
- In addition to immunoglobulins, colostrum contains any other factors that are important for immune function.
- Failure of passive transfer (FPT) is associated with an increased risk of infectious disease and mortality.
- Routine screening of all foals should be performed, in order to detect, and to allow prompt treatment of, FPT.
- Treatment of FPT is dependent on the age of the foal, but primarily involves the administration of enteral colostrum or intravenous plasma.