The Equine Neonate Failure of Passive Transfer and Use of Plasma
FAILURE OF PASSIVE TRANSFER
All foals are born,
because of their epitheliochorial placentation, with a deficiency of humoral
immunity.1 They must rely on the adequate intake of good quality colostrum
within a few hours of birth to provide essential antibodies in order to
withstand the challenges of infectious agents during the following weeks.
Unfortunately, this transfer of antibodies from dam to of offspring does not
always occur successfully and "failure of passive transfer" (FPT) is said to
exist, as depicted by the foal's serum gammaglobulin (usually specifically IgG)
level being less than 400-800mg/dl (see page 3). 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 possibly plasma) may well rectify
the situation. If, on the other hand, the foal is over 24 hours old when this
deficiency is diagnosed, the foal must be considered at risk to infection,
especially in the "high challenge" (see page 3) environment. In such
circumstances an intravenous transfusion of plasma should be considered, the
benefits of which are well documented.2,3 POLYMUNE and POLYMUNE-PLUS are two
forms of commercially available high quality equine plasma, specifically
produced for this purpose.
THE DIAGNOSIS OF
FPT
Accurately assessing the immunoglobulin status of the equine
neonate on a clinical basis cannot be accomplished. Certain factors relative to
the foaling process, such as prior leakage of "liquid" from the udder, failure
to nurse soon after birth and the presence of agalactia will warn of the
probability of low IgG levels. Veterinary Dynamics has recognized this problem
and through its research and development program has devised the GAMMA-CHECK-C
and GAMMA-CHECK-E tests to provide a simple cost effective means of
semi-quantitatively assessing colostrum and blood gammaglobulin levels. In
addition, an accurate and standardized IgG test is available in the form of the
EQUINE-RID kit. All these tests can be easily performed by either the
veterinarian or technical staff.
TREATMENT
OF FPT
Foals under 18 hours old:
High quality colostrum
(Spg. >1.060 or + Gamma-Check-C) is the method of choice. Research has shown
that 60g of good quality colostrum are needed to achieve a significant increase
in the circulating IgG level. Presently in vogue, are various non colostrum oral
forms of IgG and their efficacy awaits to be seen. What they do not contain are
all the other essential components of colostrum, such as epithelial growth
factor, transferrin, various cytokines, etc.
Foals over 24 hours old:
Plasma is the treatment of choice and has been for many years.
Commercial plasma is well proven for efficacy and safety. Reactions are rare.
With sophisticated vaccine strategies, antibodies to the common neonatal
pathogens are present in the plasma, even though it might be produced 2000 miles
from where the mare and foal are.
Other sources of IgG are now being made
available. Serum products suffer from the frequent problem of being contaminated
with endotoxin and prostaglandin metabolites,5-8 which may often cause severe
reactions. Because of USDA requirements, these pasteurized serum products often
contain damaged proteins and have abnormal electrophoretic patterns.8 For these
reasons they have to be diluted and administered very slowly.9,10 Many of the
essential cytokines present in plasma are not present in
serum.
Lyophilized IgG is now available, but again does not have the
broad spectrum of components that plasma has. Whether it will provide adequate
protection awaits to be seen. It is distinctly possible that we have become
preoccupied with IgG and we are forgetting there are many other essential
components to the healthy immune system. It could well be that it is not
sufficient just to increase the IgG level to cause the foal to stay healthy.
Time will tell!
One leading equine practitioner in Kentucky11 aptly
described plasma as "life in a bag."
EQUINE PLASMA (POLYMUNE and
POLYMUNE-PLUS)
Indications
Equine
plasma is indicated where a foal that is 24 hours old or more has been diagnosed
as having inadequate circulating immunoglobulin G levels. The definition of
"inadequate" is open to some degree of interpretation and dependent on several
factors.12 In a recent research project, 85% of foals totally deprived of
colostrum became ill within a very short period of time.13 Other studies have
shown that in the right environment foals can survive with very small amounts of
maternally derived antibodies.14 The "right" environment might, for example, be
created by one foal being in a well tended 20 acre field, with only its dam to
share the land. Conversely, a "high challenge" situation could be produced if 50
mares and foals shared the same field. 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.2-13
Generally accepted veterinary medical standards (and often
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.
Dosage
A. Oral:
Research has shown
that the amount absorbed is directly dependent on the time of administration.
Close to 100% could be absorbed if the plasma is given within the first hour or
two. This rapidly diminishes, so that only 50% is absorbed at 10 hours and less
than 20% at 15 hours. The dose required to correct complete colostrum lack is
over 60g and this will be supplied by about two liters of POLYMUNE-PLUS (see
Treatment of FPT, page 3).
B. Intravenous:
A 50 Kg foal has a
blood volume of approximately 5 liters (or 3 liters of plasma) and therefore any
transfused antibodies will be immediately distributed within this volume. The
administration of one liter of plasma containing 25 grams IgG will initially
raise the recipient's whole blood level by 5g (25 divided by 5). However, within
the 24 hours following transfusion there is some movement out of the circulation
and only about 50% remains in the vascular spaces after 24 hours. (This is why
it is important to wait at least 24 hours before measuring the IgG level after
transfusion). Therefore, after the transfusion of the liter of plasma with g
IgG, the foal's circulating whole blood level will be increased by about 2.5g/L
(250mg/dl whole blood). If we wish to express the concentration in the plasma,
then the level will be 25 divided by 2 = 1 2.5g in the blood vessels which is
now distributed within 3 liters of plasma, i.e. 4.17g per liter or 417mg/dl
plasma.
When having a test done it is important to know whether the
results are mg/dl of whole blood or plasma. As shown in the above example, there
is a 65% difference. This has been well documented in the past.15 By knowing the
initial level and the desired final level, the amount of plasma to be
administered can be calculated.
IT SHOULD BE POINTED OUT THAT ANY IgG
ADMINISTERED TO A FOAL WILL BE OF SOME BENEFIT. It is also important to realize
that passive immunoglobulin transfer is not a simple "yes" or "no" equation and
there is no absolute level of circulating IgG that will ensure the foal's
health. To afford maximum protection against disease, the immunoglobulin should
be available at the place where an organism is invading. It must also be of the
appropriate immunoglobulin type to attach to the specific invading organism and
be present in sufficient quality to neutralize the agent.16
In the
presence of sepsis, immunoglobulins are rapidly consumed having, therefore, a
very short 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 emphasized that the
sick foal would have had a lower IgG if plasma had not been given. To keep IgG
levels up in the face of rapid consumption, severely compromised foals can
require many liters over a few days.
Non-antibody factors in Polymune
As well as
specifically increasing resistance to infection by providing antibodies, plasma
also provides non-specific protection against diseases. The protection is
provided by cytokines, Iymphokines and other bioactive peptides.17 These
compounds increase the activity of neutrophils and enhance phagocytosis. Plasma
also enhances the benefits of fluid therapy, because of its albumin content. It
is indicated for intravenous use in horses of any age with hypovolemia and/or
hypoproteinemia, and as supportive therapy in major equine surgery.
Production
Veterinary Dynamics Inc. produces
normal equine plasma in California from a closed herd of donor horses, under the
regulations of the USDA and the California Department of Agriculture. Prior to
acceptance into the herd, the animals are screened by special arrangement with
the Department of Serology, University of California, Davis, the USDA and the
California State Diagnostic Laboratory. The tests ensure that these horses are
essentially free from diseases and that they are cleared as plasma
donors.
To ensure the presence of high levels of immunoglobulin
(specifically IgG), a special vaccination protocol is utilized. Accurate IgG
measurements are done on each batch using a standardized radial immunodiffusion
test. The level of IgG in the plasma ranges from 1600 >3500mg/dl. In
addition, the total protein is measured during the production stage by
refractometer and ranges from 50 g/L to 68 g/L.
Collection of plasma is
by the process of plasmapheresis, using equipment initially devised for human
donors, but with modifications to facilitate their use in large animals. This
completely closed process ensures sterility and freedom from endotoxins.
Nevertheless, each batch is also subjected to sterility tests using
thioglycollate broth. Plasma is collected directly into one liter bags which are
immediately labeled, batch numbered, packaged and placed in the freezer at-18°
C.
Specific Antibodies
As well as
providing plasma with a range of antibodies against common neonatal pathogens,
Veterinary Dynamics has the ability to produce plasma with high levels of
antibodies to specific organisms. These antibody specific plasmas are not
presently licensed by the USDA but are available in California and Europe though
our UK facility.
For many years rotavirus has been implicated as a cause
of foal diarrhea.18,19. Consequently, Veterinary Dynamics (UK) has had a vaccine
prepared by Moredun Animal Health Ltd. incorporating the equine H2 strain of the
virus. The vaccine, utilizing ISCOM technology has been used in their donors to
produce high titer rotavirus plasma. These titers are confirmed, using the
serum-virus neutralization test, by the Moredun Research Institute. This plasma
can be provided (in Europe) in pre-filled syringes for oral use or in liter bags
for intravenous use in the severely ill and dehydrated foal. We are looking at
the possibility of producing a similar product in California.
More
recently, Clostridium perfringens has been implicated in foal diarrhea20 and in
1995 donors were vaccinated with this antigen. In another situation isolates of
Rhodococcus equi, have been made into an autogenous vaccine which is used to
immunize some of our donors. The plasma subsequently produced by these donors
has then been used prophylactically. This is similar to established protocols
employed successfully in California, Texas, Kentucky, and
Brazil.21,22
Endotoxemia is a serious problem in horses of all ages and,
whilst its treatment is a controversial topic, we produce plasma containing gram
negative core antibodies by using a vaccine produced by Hygiea Biological
Laboratories, CA. In human medicine it has been documented that antiendotoxin
plasma is most beneficial when there is a concomitant bacteremia.23 In horses
good results have been obtained in a double blind study24 at U.C. Davis,
California.
Veterinary Dynamics, Inc. has been developing hyperimmune
serum to Clostridium botulinum types B and C. Type B and Type C are available on
a limited basis. There is a possibility that we could supply the type B product
for use in horses when the veterinarian client relationship is established.
Consultation is available with Dr. Denise Jones, our Director of Research. An
application for conditional use is pending with the USDA.
Storage
Plasma must be handled carefully when
frozen, as the blood transfer bags are somewhat brittle in this state and might
crack if knocked or dropped. It is advisable, therefore, to keep it packaged (as
supplied) until required. The shelf-life of the frozen product is three
years.
Administration
Plasma is
best thawed immediately prior to administration. The most convenient means is to
place the bag into warm water with a temperature of about 40°C (this will feel
like a warm shower - if you cannot keep your hand in it, it is too hot. Thawing
in water too hot will denature certain proteins and cause excessive fibrin
precipitation). Keep adding more warm water as the plasma thaws. At the correct
temperature the whole process will take about 20 minutes. Plasma that has been
thawed slowly, but not heated will have a large amount of precipitate in it.
This is called cryoprecipate and contains several important clotting factors. By
allowing plasma to warm to about body temperature this precipitate will dissolve
and the liquid should be relatively clear before administering. Occasionally
some fibrin strands are present and these are filtered out by the administration
set.
Plasma should be given USING A BLOOD ADMINISTRATION KIT WITH
APPROPRIATE FILTER (40-180 microns). It should be used straight from the bag,
with nothing added. Foals may be mildly sedated if necessary and the jugular
site prepared aseptically. It is also recommended that the skin be anaesthetized
and a 16 G x 2" catheter or similar be used. One liter of plasma can be safely
administered to a 50 Kg foal in 15-20 minutes.
Plasma which has been
thawed and not brought to body temperature can be stored in the refrigerator for
up to two weeks or refrozen. We do not recommend that you keep plasma or
refreeze it, if it has been warmed to body temperature.
Adverse Reactions
As with any biological (or
pharmaceutical) product, reactions can occur . Fortunately, the incidence with
commercially produced plasma are very rare . Over the ten years we have been
selling this product (amounting to thousands of liters) we have had only a hand
full of reactions reported. Some of those, such as reactions caused by not using
a filter are easily avoided.
There are potentially several types of
adverse reactions:
1. Volume overload - as the new born foal has a total
blood volume of about 5 liters, it is easy to understand how volume overload
might occur. A healthy foal is able to handle the transfusion of 1 liter of
plasma in about 15-20 minutes, but 2 liters should be given over a minimum of
two hours. A sick and compromised foal will require much longer for the
administration of the same volume. Signs of volume overload include
hyperventilation, tachycardia and sweating. The rate of administration must be
immediately slowed down if these signs appear and stopped completely if these
signs do not quickly abate.
2. Anaphylaxis - there are two types:
A -this usually occurs when the foal is in some way sensitized to the
plasma being transfused. In the neonate the likely cause of this is by receiving
sensitizing antibodies through the colostrum.25 We are aware of several
instances where this appears to have occurred in mares with previous histories
of severe dystocia. It is theorized that the dystocia leads to the mare being
exposed to foreign (foal) antigens and then producing antibodies to these. Signs
includes hyperventilation, frothing at the mouth and gurgling sounds from the
lungs. The transfusion should be stopped immediately and epinephrine and
anti-inflammatory drugs administered. Forced ventilation, thoracic massage and
oxygen might be needed. Mares producing such foals do so year after year and if
a transfusion is essential in a subsequent foal, intradermal skin testing could
be performed with the plasma prior to transfusion.
B -if using plasma
from a donor not screened for red cell antibodies, then agglutination and/or
hemolysis might occur. Signs include hyperventilation, but not profound
bubbling. This is not a problem with commercial plasma from screened
donors.
3. Fibrin entering the system - by not using a filter. Symptoms
include rapid dilation of the pupil, apnoea and sudden death. It is likely that
a fibrin clump enters the cardiac circulation causing myocardial
ischemia.
All these problems are easily avoided by using properly
harvested plasma from screened donors. The only occasion which might cause an
unexpected problem is when a foal is transfused born to a mare with unknown
hypersensitivity from a previous foaling.
Delivery
Plasma is shipped frozen in insulated
containers by express courier to reach destinations in most parts of the USA by
noon the following day. (Orders must be placed by 3 p.m. to ensure next day
delivery). Special arrangements can be made for weekend delivery and when
emergency situations arise.
LEGEND
a. Gamma Check-E Veterinary Dynamics, Inc. San Luis Obispo, CA
b. Gamma Check-C Veterinary Dynamics, Inc. San Luis Obispo, CA
c. Colostrometer Juergensen Loveland, CO
d. Equine RID Veterinary Dynamics, Inc. San Luis Obispo, CA
e. POLYMUNE and
POLYMUNE-PLUS Veterinary Dynamics, Inc. San Luis Obispo, CA
REFERENCES
1. Jeffcott LB: Some practical aspects of the transfer of passive immunity to newborn foals. Equine Vet J, 1974; 6:109-115.
2. Perryman LE, and Crawford TB: Diagnosis and management of immune system failures in foals. Am Assoc Equine Pract, 1979; 235-244.
3. Rumbaugh GE, et al: Identification and treatment of colostrum deficient foals. J Am Vet Med Assoc, 1979; 174:273-275.
4. Jones D, and Brook D: Investigation of the GAMMA-CHECK-C test as a means of evaluating IgG levels in Equine Colostrum. J of Eq Vet Sc, 1995; 15: 269-273.
5. Durando MM, et al.: Effects of polymyxin B and Salmonella typhimurium antiserum on horses given endotoxin intravenously. Am J Vet Res, 1994; 55 (7):921-926.
6. Mouchawar AM, et al.: Serum but not Plasma Produces Injury in the Perfused Rabbit Lung. Anesth Analg, 1994; 79:40-45.
7. Cullor J: Dept of Pathology, UC Davis, Davis, CA. Personal Communication, 1994.
8. Brown CM: Uncertainties in the significance, diagnosis and treatment of FPT in foals. ISVP Newsletter, Ed. Shauna Spurlock, Veterinary Learning Systems, New Jersey, 1991.
9. Immvac, Inc., Columbia, Missouri. Instructions for Using Endoserum
10. Sera, Inc., Kansas. Instructions for using Seramune
11. Byars TD: Personal communication, Lexington, KY, 1995
12. Koterba AM, Brewer B, and Drummond WH: Prevention and control of infection. Vet Clin North Am Equine Pract, 1985; 1:41-50.
13. Robinson JA et al.: A prospective study of septicemia in colostrum-deprived foals. Equine Vet J, 1993; 25:214-219.
14. Baldwin JL et al.: Immunoglobuiin G and early survival of foals: a three year field study. Proc Am Assoc Equine Pract, 1989; 35:179-185.
15. White SL: Exogenous IgG in the treatment of foals with failure of passive transfer and/or sepsis. In: Sixth Annu ACVIM Proc, 1988; 145.
16. Garry F, and Wells S: Colostrum Management: How Good is Your Program. Second Western Large Herd Dairy Management Conference, Las Vegas, NV, 1995.
17. Harris JA, et al.: Effects of ant-R.equi hyperimmune serum on equine neonatal alveolar macrophage function. In: Third Int Conf of ISVP, 1993; 16-17.
18. Dugdale D: Outbreak of rotavirus diarrhoea in two successive years on a stud farm. Equine Vet Education, 1992; 4:233-236.
19. Dwyer RM, et al.: Infectious foal diarrhea: A three year study of epidemiology and prevention. Proc Am Coll Vet Int Med, 1990; 8:569-57.
20. Anon; Foal Diarrhoea, Animal Health trust, Newmarket. England. Scientific Report, 1992-1993.
21. Veterinary Dynamics Newsletter, 1994. San Luis Obispo, California.
22. Madigan JE and Muller N: Acquisition of passive immunity against Rhodococcus equi by administration of hyperimmune plasma. Proceedings 35th MEP Convention, 1989; 35:521-523.
23. Buamgartner JD: Anti-endotoxin antibodies as treatment for sepsis - lessons to be learnt. Reviews in Med Microbiol, 1994; S3:183-190.
24. Spier SJ, et al.: Protection against clinical endotoxemia in horse by using plasma containing antibodies to an Rc mutant E.coli (J5). Circular. Shock 1989; 28:235-248.
25. Tizard I: Personal communication, Texas A and M University, Texas, USA, 1994.
VETERINARY DYNAMICS INC. 1535 TEMPLETON ROAD TEMPLETON, CALIFORNIA 93465
Telephone 805 434-0321