Failure of Passive Transfer

Immunodeficiency

All foals are born with a deficiency of humoral antibody (ref 1). They rely on the adequate intake of good quality colostrum within a few hours of birth to supply significant amounts of IgG and IgG(T) and lesser amounts of IgM and other immunoglobulin classes, to provide significant transient protection against infectious agents (ref 2,3,4,5). Unfortunately, this transfer of antibodies from dam to offspring does not always occur successfully, resulting in “failure of passive transfer” (FPT), as depicted by foal serum gammaglobulin levels (usually specifically IgG) of less than 4g/l. If this deficiency is confirmed before the gut’s ability to absorb antibodies ceases (12-18 hours of age), oral supplementation of good quality colostrum or plasma may well rectify the situation. If, on the other hand, the foal is over 12-18 hours old when this deficiency is diagnosed, the foal has to be considered at risk to infection, especially in a “high challenge” environment. In such circumstances transfusion of plasma should be considered, the benefits of which are well documented (ref 6,7).

Any steps which the veterinary surgeon in practice can take to improve the welfare of the equine neonate by decreasing the susceptibility to painful, debilitating and potentially fatal infectious disease such as septicaemia, joint-ill, navel-ill diarrhoea and pneumonia must be given serious consideration

Indications for Plasma Transfusion

Equine plasma transfusion is indicated where a foal of 24 hours old or more has been diagnosed as having inadequate circulating gammaglobulin levels. The definition of “inadequate” is open to some degree of interpretation and dependent on several factors (8). In one research project, 85% of foals totally deprived of colostrum became ill within a very short period of time (9). Other studies have shown that in the right environment foals can survive with very small amounts of maternally derived antibodies (10). For example the “right” environment, might be created by one foal being in a well tended 20 acre field, with only its dam to share the pasture. Conversely, a “high challenge” situation could be produced if 50 mares and foals shared the same area. The “right” environment is, unfortunately, not present in most situations and the majority of foals with FPT do succumb to some form of infection during the early weeks of life (2,3,4,5,6). Generally veterinary medical standards (and often some insurance company requirements) now dictate that foals be checked for IgG within the first day or so of life and those showing a deficiency given some form of supplemental antibodies.

Immunoglobulin G

The main use for equine plasma is as a source of equine IgG when used prophylactically in foals with failure of passive transfer or partial failure of passive transfer, ie circulating gammaglobulin levels of less than 8g/l (ref 7, 8). IgG is the immunoglobulin isotype found in the highest concentration in blood and for this reason plays a major role in antibody mediated defence mechanisms. Because of its size it can escape from blood vessels more easily than other immunoglobulin molecules thus readily participating in the defence of tissue spaces and body surfaces. IgG can opsonise, agglutinate and precipitate antigen but it can activate the complement cascade only if sufficient molecules have accumulated in a correct configuration on the antigen surface.

The IgG molecule is a Y shaped structure of linked polypeptide chains. Each of the two branches of the Y is the Fab fragment because it has the ability to bind antigen, while the “body” of the Y is called the Fc fragment and it has the ability to bind to receptors on the surface of cells. This part is crucial in activating the complement cascade, which leads to disruption of cell membranes and destruction of invading micro-organisms. It is from this background that HYPERMUNE is harvested and stored to ensure these desirable properties of IgG are preserved. Although there are a number of beneficial proteins in equine plasma IgG has always been the focus of attention because not only is it of major importance but also it is relatively easily measured in foal blood, and in equine plasma.

Dosage

A 50kg foal has a plasma volume of approximately four litres and therefore any transfused antibodies will be immediately distributed within this volume. The administration of one litre of plasma containing 24g IgG, HYPERMUNE’s minimum level, will initially raise the recipient’s blood level by 6g/l (24 divided by 4). However, within 24 hours following transfusion there is some movement out of the circulation and only about 50% remains in the vascular system after 24 hours. (This is why it is important to wait approximately 24 hours before measuring the IgG level after transfusion). Therefore, after the transfusion of the litre of plasma with the 24g IgG, the foal’s circulating level will be increased by about 3g/l. This has been documented in the past (ref 11). By accurately knowing the initial level and the desired final level the amount of plasma to be administered can be calculated. It has been reported that in a healthy 45kg foal a rise of about 1-2 g/l for every 10g of IgG administered might be expected and furthermore, therefore, a foal with an IgG level of 0g/l would require 20- 40g IgG (ref 12).This may be provided by infusing up to four litres of plasma from a normal resting horse but in a foal this would cause volume overload problems. The design of HYPERMUNE equine plasma is to overcome this problem by providing a greater concentration of IgG per litre using hyper-immunised horses.

In the presence of sepsis immunoglobulins are rapidly consumed resulting in a shortened half-life. (Plasma proteins provided by transfusion normally have a half-life similar to autologous proteins, which in the case of immunoglobulins is about 21 days). In the presence of infection the half life might be as low as a few hours and a plasma transfusion might not appear to give the expected increase in IgG when given to a sick foal. It needs to be emphasised that the sick foal would have had a lower IgG if plasma had not been given. To keep IgG levels sustained in the face of rapid consumption, severely compromised foals can require a number of litres over a few days.

Any steps which the veterinary surgeon in practice can take to improve the welfare of the equine neonate by decreasing the susceptibility to painful, debilitating and potentially fatal infectious disease such as septicaemia, joint-ill, navel-ill diarrhoea and pneumonia must be given serious consideration. HYPERMUNE provides that resource for the foal which has failure of passive transfer of colostral immunity. The intravenous administration of equine plasma harvested under widely ranging conditions is accepted and utilised throughout the world.

The Practical Use of HYPERMUNE

The veterinary application of equine plasma for the treatment of FPT in foals is not new, having been recommended for over a decade in text books (refs 13,14,15), conference proceedings (ref 16), satellite article (ref 17), practice tip (ref 12), and a manual of equine neonatal medicine (ref 18). In the United States, where commercial equine plasma usage has been well established for much longer than in the United Kingdom the whole matter was reviewed in 1994 (ref 19), with the conclusion that the process of plasmapheresis has made the use of equine plasma safe and efficacious. The review states that research with equine plasma has shown that treatment of disease or protection against disease is in proportion to the amount of IgG in the plasma. It also summarises that one of the earliest studies reported using equine plasma in 1984 saw 119 transfusions being made in a variety of equine disease states which included FPT and septicaemia.

In the United Kingdom two recent publications (ref 17, 12) , advocate that the administration of plasma to a foal can be a life saving procedure and that plasma administration has important applications in the therapeutic and prophylactic management of conditions in equine practice.

The equipment and basic technique employed by Veterinary Immunogenics Ltd (Veterinary Immunogenics) were “imported” from the United States in 1992. At that time, commercial equine plasma had been available for more than five years in the United States and was being used at the rate of well over 5000 litres per year in that country alone. Over recent years Veterinary Immunogenics has refined the techniques and adopted validated standardised procedures to ensure maximum product quality, safety and efficacy. The claim that HYPERMUNE supplements foal IgG is supported by four field studies involving just under 100 foals. Veterinary Immunogenics Ltd continues to promote immunoprophylaxis and seeks to produce the finest horse plasma in the world.

Regulatory Authorisation

In September 2002, Veterinary Immunogenics Ltd was granted a UK Medicines Control Agency licence, ML 18513/1, to manufacture the immunological veterinary product -; Veterinary Immunogenics was granted a Marketing Authorisation for HYPERMUNE in January 2003, and renewed for life in January 2008 - Vm 18513/4000. Veterinary Immunogenics was granted a UK National Marketing Authorisation for HYPERMUNE-RE in April 2007 - Vm 18513/4001 and through the mutual Recognition procedure a Mutually Recognised authorisation in the UK and Ireland in August 2008.

References