Download Review of Equine Acute-Phase Proteins

MEDICINE—INFECTIOUS DISEASES
Review of Equine Acute-Phase Proteins
Stine Jacobsen, DVM, PhD
Plasma concentrations of acute-phase proteins (APPs) increase during the acute-phase response to
every process that leads to tissue damage (e.g., infections, trauma, surgery, and neoplasia). Measurements of APPs may be useful for diagnosing the presence of inflammation and tissue damage,
prognostication, monitoring the effect of the therapy and the occurrence of post-operative complications or relapse, and monitoring herd health. APPs are potentially valuable adjuvants to clinical
assessment of a patient. Author’s address: Department of Large Animal Sciences (Large Animal
Surgery), Faculty of Life Sciences, University of Copenhagen, Dyrlaegevej 48, DK-1870 Frederiksberg
C, Copenhagen, Denmark; e-mail: [email protected]. © 2007 AAEP.
1.
Introduction
Monitoring the inflammatory response can be a clinical challenge, because signs of inflammation do not
always manifest clinically. Under certain circumstances, blood-biochemical and/or hematological testing may be necessary to identify indiscernible
inflammatory disease. Within the last couple of decades, interest has focused on the potential use of the
acute phase proteins (APPs) as indicators of the presence, degree, and time course of inflammation, because these proteins are released in large quantities
into the blood stream in response to infection and
tissue injury. In humans, APP measurements are
used for routine assessment of inflammatory status;
however, in horses, the APP response has only been
investigated to a limited degree, which precludes the
use of APPs in evidence-based equine medicine. The
purpose of this paper is to review what is currently
Information contained in this paper has been reprinted, with
permission from EVJ Ltd., from Jacobsen S and Andersen PH. The
acute phase protein serum amyloid A (SAA) as a marker of inflammation in horses. Equine Vet Educ. (2007) 19(1)36 – 46.
NOTES
230
2007 Ⲑ Vol. 53 Ⲑ AAEP PROCEEDINGS
known about the equine APPs and to discuss their
possible applications in the equine clinic.
2.
The Acute-Phase Response
The acute-phase response (APR) is a complex set of
inflammatory reactions that occur after injury or
infection. It is induced by all processes that lead to
tissue damage (bacterial and viral infection, parasite infestation, trauma, surgery, ischemic necrosis,
burns, and neoplasia).1 The APR is initiated when
cells and tissues are injured. Injury elicits production of a large number of inflammatory mediators
among which the cytokines play very important
roles.2 The cytokines initiate the APR cascade
through stimulation of several cell types. A central
pathophysiological step of the APR is hepatic synthesis and as a result, increased plasma concentrations of APPs. Recent studies have shown that
extrahepatic tissues can also be stimulated by cytokines to produce APPs.3–5
3.
The APPs
APPs are proteins that have serum concentration
changes of at least 25% during the APR.6 Levels of
MEDICINE—INFECTIOUS DISEASES
Table 1.
Positive and Negative Acute Phase Proteins in the Horse
Acute Phase Protein
Major (10 to several hundred or thousand times
increase)
Serum amyloid A (mg/L)
Moderate (5–10 times increase) and minor (0.5–5
times increase)
Haptoglobin (mg/l)
␣1-acid glycoprotein (mg/l)
C-reactive protein (mg/l)
Fibrinogen (mg/l)
Ceruloplasmin (mg/l)
Negative (decrease)
Albumin (g/l)
Normal
Plasma
Concentration*
Plasma Concentrations
Reported for
Inflammatory
Conditions*
0.5–20
50–800
200–1000
70–90
7.5
2000–4000
300–400
400–2700
100–250
10–35
3000–11.000
700–900
12–24
24
24
24–72
120
72–120
72
72–120
72–144
168–336
27.5
144
192–240
30
Response Time (h)
Start
Increase
Peak
6–12
48
Based on Smith and Cipriano (1987);16 Pepys et al. (1989);10 Auer et al. (1989);17 Takiguchi et al. (1990);13 Okumura et al. (1991);15
Yamashita et al. (1991);11 Taira et al. (1992a);12 Taira et al. (1992b);14 Nunokawa et al. (1993);9 Fagliari et al. (1998);22 Hultén et al.
(2002);24 Jacobsen et al. (2005).38
Reprinted with permission from Equine Veterinary Education.21
* Concentrations depend to some extent on the assay used and may thus differ slightly between studies.
positive APPs increase during the APR. The group
of positive APPs is further subdivided based on their
pattern of response to stimulation. The major positive APPs have very low or undetectable levels in
healthy individuals, and their serum concentrations
increase ⬎100 times during the APR (Table 1).
The moderate or minor APPs are present in serum of
healthy individuals, and their concentrations increase 1–10 times during the APR (Table 1). The
negative APPs are proteins with plasma concentrations that decrease during the APR. In horses and
many other species, albumin is a negative APP.7
During the APR, the demand for amino acids for
synthesis of the positive APPs is markedly increased, which causes down-regulation of hepatic
albumin synthesis and shunting of amino acids into
synthesis of positive APPs.8
The different APPs have different kinetic profiles
(Table 1). Some increase within a few hours of
infection or tissue injury and reach peak values
within 1–2 days, whereas others have a slower increase and remain elevated for longer periods of
time. In horses, serum amyloid A (SAA) is an example of the former group.9,10 Haptoglobin, ␣1-glycoprotein (orosomucoid), and C-reactive protein all
have intermediate response times.7,11–14 Fibrinogen and ceruloplasmin concentrations peak 7–10
days after an inflammatory stimulus and may remain elevated for several weeks.15–17
4.
APPs in the Equine Clinic
The possible applications of APPs in the veterinary
clinical chemistry have been comprehensively reviewed.18,19 However, the equine APP response
has not been investigated thoroughly, and these reviews mainly concern species other than the horse.
Use of fibrinogen and SAA for detection of inflam-
mation specifically in horses has been reviewed by
Andrews et al.20 and by Jacobsen and Andersen.21
Cytokines inducing hepatic APP synthesis are released from inflamed or injured tissue independent
of the cause of the tissue injury. As a consequence
of this, APPs are non-specific markers of inflammation and cannot be used for making etiological diagnoses. Therefore, measurements of APPs are
mainly relevant for the following purposes: diagnosing the presence of inflammation, prognostication, monitoring the effect of the therapy and the
occurrence of post-operative complications or relapse, and monitoring herd health.
Diagnosing
In horses, APP levels have been reported to be elevated during bacterial and viral infections (such as
infectious arthritis, strangles, pneumonia, sepsis,
enteritis, and herpes and influenza virus infection),
during parasite infestations, after surgery, after
parturition, and when colic, abscesses, laminitis, or
grass sickness are present.7,9 –17,22–31 Because of
its role in clearance of free iron and hemoglobin from
the circulation, haptoglobin concentrations decrease
in horses with intravascular and extravascular hemolytic anemia. Serum haptoglobin has been reported to be an early and sensitive indicator of
hemolysis and is useful for diagnosing and prognosticating anemias without clear pathogenesis.32
The diagnostics potential of APPs may be particularly relevant for differentiating between infectious and non-infectious diseases that cause
weakness in neonatal foals. In this type of patient,
clinical signs are often non-specific, and diseases in
neonates are, therefore, notoriously difficult to diagnose. Remarkably high plasma levels of SAA have
been detected in foals with sepsis, but SAA levels
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231
MEDICINE—INFECTIOUS DISEASES
are also increased in foals suffering from local infections.23,33,34 Serum concentrations of SAA in foals
with non-infectious causes of weakness (e.g., prematurity, failure of passive transfer, neonatal maladjustment syndrome, isoerythrolysis, and meconium
colic) have been reported to be in the normal
range23,34 or slightly elevated.33 Stoneham et al.34
suggested that a cut-off value of 100 mg/l could be
used to differentiate infectious from non-infectious
cases and that inclusion of SAA in sepsis-scoring
systems might improve diagnosing of neonatal sepsis and as a result, the chance of successful treatment. Hultén and Demmers23 showed that SAA
was much more accurate in distinguishing infectious from non-infectious diseases than plasma-fibrinogen concentrations and leukocyte counts,
whereas a study on Rhodococcus equi infection
showed that total leukocyte count had significantly
higher diagnostic performance than fibrinogen,
which had low sensitivity and specificity in early
identification of infected foals.35
Prognostication
The magnitude and duration of the APP response
have been shown to reflect the severity of infection
and to correlate with the amount of underlying tissue damage and inflammation in cattle and humans.36,37 Therefore, APP levels may serve as
indicators of prognosis. In horses, it has been
shown that intra-articular injection of 3 ␮g of lipopolysaccharide elicits a larger SAA response than
injection of 1 ␮g, which suggests that APP concentrations reflect the extent of the underlying inflammation in the horse.38
In humans and dogs, levels of SAA and C-reactive
protein have been used for prediction of outcome and
post-operative complications during neoplastic disease, surgery, and burns and for diagnosing relapse
during immune-mediated arthritis.39 – 41 In sheep
with dystocia, high haptoglobin levels have been
shown to indicate dead lambs in utero and consequently, increased surgical risk and poor prognosis.42 A recent study31 of horses hospitalized
with colic showed that SAA levels at admission
were higher in non-survivors than in survivors.
Although this finding suggests that SAA measurements may be used for prediction of prognosis,
concentrations differed only slightly between nonsurvivors and survivors (median concentrations in
the two groups were 10.8 and 1.4 mg/l, respectively), and Vandenplas et al.31 concluded that
sensitivity and specificity did not seem to be high
enough to be clinically useful. In a study on critically ill and septic foals, high fibrinogen concentration was among the most significant predictors
of mortality.43 APP measurements might become
a valuable tool for veterinarians in advising horse
owners on treatment of their animals.
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2007 Ⲑ Vol. 53 Ⲑ AAEP PROCEEDINGS
Monitoring
The major equine APP SAA seems particularly
suited for real-time monitoring of inflammatory activity.21 The low or undetectable SAA levels in
healthy horses facilitate interpretation of mildly elevated concentrations, and the quick response time
and short half-life of SAA cause its blood levels to
increase quickly after an inflammatory stimulus has
occurred38 and to decrease in close parallel with
successful treatment and resolution of disease.9,23
This is in contrast to fibrinogen and haptoglobin,
which are less suited for monitoring of the disease
activity. Fibrinogen and haptoglobin are present
in high levels in blood of healthy horses, and their
amplitude of response is much lower than that of
SAA (Table 1). Moreover, it takes days for their
levels to increase after an inflammatory stimulus,
and concentrations stay elevated for an extended
period of time after the disease has been resolved.7,12 Certain pathological conditions (diseases characterized by hemolysis, disseminated
intravascular coagulation, or changes in vascular
permeability) may cause levels of haptoglobin and
fibrinogen to decrease,20,32 thus masking increases
induced by inflammatory processes.
Serum amyloid A seems to be able to monitor
response to treatment of infections in the respiratory tract. A study on Rhodococcus equi pneumonia showed that foals had elevated plasma SAA
and fibrinogen levels on admission to the hospital.
Whereas SAA levels decreased with successful treatment and clinical improvement, fibrinogen levels
were still high on discharge.23 APP levels may also
be an aid in determining when a horse can return
to training after having recovered from an airway
infection. In horses with a particularly severe influenza-virus infection or in horses suspected of having contracted secondary bacterial infection, SAA
levels remained elevated for an extended period of
time compared with horses with a milder course of
infection.25
Surgery has been shown to induce an APR and
cause elevated plasma levels of SAA, fibrinogen,
haptoglobin, ␣1-acid glycoprotein, and ceruloplasmin.11,12,14,15,26,30,44 Two small studies (each with
only two horses) suggested that general anesthesia
alone had no effect on SAA and fibrinogen levels.7,10
The normal post-operative APP response has a riseand-fall pattern, and sustained increases in APP levels
post-operatively may indicate post-operative complications. In castrated horses, high SAA concentrations 8
days post-surgery suggested that surgery had been
complicated by excessive inflammation/infection.26
Herd Health
Measurements of APPs in large groups of horses
could be useful for several purposes. Serum amyloid A measurements may be used to monitor spread
of infections through farms or stables; levels remained undetectable in horses, which (despite being
in contact with infections such as herpes virus or
MEDICINE—INFECTIOUS DISEASES
10
strangles) did not contract the disease.
This
could be useful when setting up quarantines.
APPs have been suggested to be sensitive markers
of subclinical disease in cattle.45 This has not been
investigated in horses. In this context, APP measurements might be useful for routine monitoring of
health status in race and performance horses, thus
avoiding that subclinically ill horses are subjected to
the stress of transportation, competitions, and races.
Detection of subclinical disorders could serve as a
basis for advice to trainers by providing a management tool for adjustments of training intensity that
would potentially decrease the risk of horses breaking down.
It is not yet clear if routine APP measurements
can be used for detection of disease in horse herds.
A study on Rhodococcus equi pneumonia in foals
showed that SAA measurements in bimonthly blood
samples could not be used as a screening test for the
early detection of pneumonia,46 but it was not clear
if the low sensitivity resulted from long sampling
intervals, misclassification of infection status, or
Rhodococcus equi-infected foals having too small of a
SAA response.
5.
Extrahepatic Production of APPs
In horses as well as other species, SAA synthesis has
been shown to take place in several cell types other
than hepatocytes during acute-phase states.3–5
This extrahepatic synthesis occurs particularly in
endothelial cells and epithelia of organs communicating with the external environment (e.g., the gastro-intestinal tract, the mammary gland, and the
airways), which may suggest that SAA plays a role
in host-defense mechanisms and local protection
against invading microorganisms. In horses, SAA
is synthesized locally in the mammary gland and in
joints, and the protein has been shown in normal
colostrum and synovial fluid from horses with experimentally induced arthritis.4,27 It has been shown
that SAA levels in synovial fluid can help distinguish infectious from non-infectious (with less inflammation) joint disease, and when synovial fluid
SAA levels were measured sequentially in the same
patient, levels reflected effect of treatment.27
Measuring local APP levels improves precision of
diagnosis, because it provides information on inflammatory/infectious status of the particular organ
of interest. However, this potential has been explored only to a very limited degree, and much more
research is needed in this field.
6.
Measuring Equine APPs
Several methods for measuring equine APPs have
been developed, including enzyme-linked immunosorbent assay for SAA,44,47 slide reversed passive latex
agglutination test for SAA,48 single radial immunodiffusion for SAA, haptoglobin, C-reactive protein, ␣1acid glycoprotein and ceruloplasmin,9,11,12,14,15
electroimmunoassay for SAA,10,33 hemoglobin-binding
capacity assays for haptoglobin,32,49 and latex aggluti-
nation immunoturbidometric assay for SAA and haptoglobin.34,50,51 Haptoglobin and SAA assays
developed for use in multiple species including the
horse are commercially available,a but equine validation studies for these assays are not yet available.
The above mentioned assays are mainly relevant for
research purposes, but recently, a test system developed for use in equine practice and small diagnostic
laboratories has become available in Scandinavia and
the United Kingdom.b This system allows serum
concentrations of SAA and haptoglobin to be measured
within 30 min, and preliminary data show that concentrations are measured accurately and precisely.c
A human SAA assayd for use in larger diagnostic laboratories has been validated in the horse51 and is commercially available in the United Kingdom.
Several assays are available for assessment of
fibrinogen. It may be assessed with sufficient precision by heat-precipitation methods. These are
commonly used methods in the equine practice, because they are quick and do not require specialized
equipment.20 Also, the glutaraldehyde teste can be
used for measuring combined levels of globulins and
fibrinogen
semiquantitatively. Glutaraldehyde
binds free amino groups in fibrinogen and immunoglobulin and as a result, creates a clot; the clotting
time of the test estimates the concentrations of inflammatory proteins. However, a study by Brink et
al.52 showed that the test was only moderately able
to differentiate acute and chronic inflammation in
horses and that clotting time was correlated to globulin but not to fibrinogen levels. Before further
studies are available, this test should be used
cautiously.
It is important to keep in mind that APP concentrations measured by different assays are not directly comparable, and therefore, absolute
concentrations and cut-off values may differ between different studies. Also, age, gender, and
physiological condition of the horse should be considered when interpreting a measured APP concentration. Small and seemingly unimportant, yet
statistically significant, differences in serum concentrations of C-reactive protein, haptoglobin, ceruloplasmin, and ␣1-acid glycoprotein have been shown
between different age groups, between males and
females, and between pregnant and non-pregnant
mares.11,12,14,15 Most studies show no differences
in SAA and haptoglobin levels between neonatal
foals and older horses.30,33,34
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