Age-related changes in the concentrations of evaluated acute phase proteins in clinically healthy calves from the 1st till 6th month of age 
The acute phase response is a nonspecific and complex reaction of an organism that occurs shortly after any tissue injury. The origin of this response can be attributable to infectious, traumatic, immunologic, neoplastic, or other causes, in order to restore homeostasis, reduce tissue damage, and to remove the cause of disturbances . The acute phase response is characterized by a number of different systemic effects, a range of metabolic activities and alterations in a wide variety of biochemical processes. One of the most important metabolic changes is the strongly increased (or decreased) production and secretion of some plasma proteins from the liver, the acute phase proteins . The acute phase response is a very fast response, developing with increased concentrations of acute phase proteins within a few hours, which remain elevated as long as the inflammatory stimulus persists . For this reason, they represent the ideal tool for the early identification of inflammation or injury, and for monitoring the outcome of disease processes. Unfortunately, acute phase proteins are poorly specific, since they increase in the presence of inflammation independent of the agent responsible, but the increase in their concentrations indicates that „something“ is happening in the body, and should lead clinician to investigate the site, type and severity of the inflammation (complete clinico-pathological approach), to identify the pathogen responsible (specific diagnostic methods), and to follow-up the treatment.
Acute phase proteins have been studied widely in human medicine, especially as biomarkers of diseases, inflammatory processes and various infections, to diagnose and monitor the success of diseases in clinical praxis [4,5]. However, they have been relatively under-utilised in the veterinary medicine, and the possible influence of inflammatory conditions on the concentrations of these proteins, and they use as indicators in the monitoring of animal health and detection of diseases in veterinary clinical practice, especially in farm animal medicine is less well documented. For this reason, the main purpose of this article is to provide an integrated overview about the diagnostically valuable acute phase proteins in farm animals, to update the knowledge about their usefulness in the detection and diagnosis of various economically important diseases of ruminants and swine, and present some new knowledge regarding their clinical applicability and methods for determination.
2. The acute phase response
The acute phase response is a complex early-defense system induced by any process that leads to tissue damage, e.g. bacterial and viral infection, inflammation, parasite infestation, trauma, surgery, ischemic necrosis, burns, neoplastic growth . The reactions of the acute phase response are part of the non-specific immune system and thus the first line of defense against invading pathogens, which is responsible for the survival of the host during the critical early stages of the attack. It is designed to hold the infection in check until the adaptive, highly specialized immune response is initiated . The acute phase response is a cascade of host responses with the goal of reestablishing the homeostasis, to remove the cause of disturbance and promote the healing process .
The pathogenesis of the acute phase response begins within inflammatory sites, where cells involved in the innate immune response (i.e. macrophages, monocytes) produce and release a vast number of inflammatory mediators, among which the cytokines (such as interleukin-1, interleukin-6 and tumor necrosis factor-α) play very important roles . These cytokines influence organs involved in homeostasis, such as the central nervous system (CNS), the autonomic nervous system and the adrenal gland, to establish a rapid and intense protective or reactive response . Cytokines induce a cascade of events which potentiate the appearance of the main clinical changes charecterized by fever, anorexia or weight loss . In addition, the cytokines activate receptors on different target cells leading to systemic inflammatory reactions, including hormonal or metabolic, and resulting in a number of biochemical changes . These symptoms reflect multiple changes in the homeostatic control of the diseased animals, such as increased production of adrenocorticotrophic hormone and glucocorticoids, activation of the complement cascade and blood coagulation system, decreased serum concentrations of calcium, zinc, iron, vitamin A and α-tocopherol, and changes in the concentrations of some plasma proteins . One of the most important metabolic changes is the strongly increased synthesis of a group of plasma proteins, namely acute phase proteins, by the liver .
3. Acute phase proteins
In general, the acute phase proteins are a group of blood proteins that change in concentrations in animals subjected to external or internal challenges, such as infection, inflammation, trauma or stress . Acute phase proteins can be classified according to the magnitude of the increase (positive acute phase proteins) or decrease (negative acute phase proteins) in their serum concentrations during the acute phase response . They are further classified as major, moderate, or minor, depending on their responsibility. Major proteins represent those that increase 10- to 100-fold, moderate proteins increase 2- to 10-fold, and minor proteins are characterized with only a slight increase . Major proteins often are observed to increase markedly within the first 24 – 48 hours after the triggering event and often have a rapid decline due to their very short half-life. Moderate and minor proteins follow in magnitude of response and may both increase more slowly and be more prolonged in duration, depending on the status of the triggering event . Moderate and minor acute phase proteins may be observed more often during chronic inflammatory processes . In these cases, an aberrant continuation of some aspects of the acute phase response may contribute to the underlying tissue damage, which accompanies the disease and also may lead to further complications, for example protein deposition such as reactive amyloidosis .
Generally, the main function of acute phase proteins is to defend the host against pathological damage and assist in the restoration of the homeostasis. Some of the acute phase proteins (α1-antitrypsin, α2-macroglobulin) have anti-protease activity designed to inhibit proteases released by phagocytes or pathogens to minimize damage to normal tissues . Another acute phase proteins (haptoglobin, serum amyloid A, C-reactive protein) have scavenging activities and bind metabolites released from cellular degradation so they can re-enter host metabolic processes rather than be utilized by pathogen . Others (α1-acid glycoprotein) are characterized by anti-bacterial activity and by the ability to influence the course of the immune response .
Despite the uniform nature of the acute phase response, there are numerous differences in the acute phase characteristics between different animal species . The important concept is that each animal species has its own major acute phase proteins that must be considered the markers of choice for diagnostic purposes. Ruminants are significantly different to other species in their acute phase response, in that haptoglobin (Hp) and serum amyloid A (SAA) are the major acute phase proteins . On the other hand, in pigs, significant increases of C-reactive protein have been detected after an inflammatory stimulus .
4. The diagnostic utility of acute phase proteins in the veterinary practice
It is important to recognize that acute phase protein concentrations are elevated in animals with many different diseases, having very poor diagnostic specificity in detecting the cause, so they can not be used as the primary diagnostic test for a particular disease. However, they have very high sensitivity in detecting many conditions that alter the health of the animal and in providing evidence that an animal has subclinical inflammation or infection . It was reported by Kent  that acute phase proteins quickly and precisely demonstrate the presence of infectious and inflammatory conditions, but not the cause. A very interesting characteristic of the acute phase proteins is the possibility of detecting subclinical diseases . Petersen et al.  stated also that acute phase proteins can detect the presence of subclinical disease which is the cause of reduced growth rate and losses in the production. In the clinical field, acute phase proteins may serve as indicators of prognosis and effect of treatment. The magnitude and duration of the acute phase response reflect the severity of the infection and underlying tissue damage 
Practical uses and advantages of acute phase protein assays in small animals have been described and demonstrated in a large number of scientific reports published in a last few years. However, clinical application of acute phase proteins in large animals has not been sufficiently standardized in routine practice. The possible use of acute phase proteins in ruminants and swine has been investigated in various inflammatory and non-inflammatory conditions. However, there are many more areas of enquiry which can be pursued to deepen our knowledge about the acute phase response and also to develop novel applications for the acute phase proteins, e.g. during some less frequently studied diseases of young (diarrhoea, omphalophlebitis) and adult cattle (laminitis, mastitis), as well as not only in acute infections, but also in chronic inflammatory conditions. Moreover, the concentrations of acute phase proteins must be interpreted in the view of many other influences not associated with diseases. The age of evaluated animals, parturition, the transition of pregnancy to lactation are important factors that may affect the concentrations of frequently analyzed biochemical variables, including the concentrations of acute phase proteins. Considering that the evaluation of acute phase proteins would be important diagnostic aid available to clinicians, their usefulness for diagnosis and prognosis of various disorders and diseases in cattle and swine will be discussed, including the influence of some physiologic conditions on their values.
4.1. The effect of age on the concentrations of acute phase proteins
After birth, newborns and young animals go through a period of rapid growth and development, and adapt to life outside the uterus. This transition from foetal to neonatal life and then from newborn to young animal necessitates major physiological adjustments . Young calves must adapt to various environmental factors, including nutrition which changes from a primarily carbohydrate-based energy supply during the foetal period to a high fat and relatively low carbohydrate nutritional energy supply in colostrum and milk, and then from milk to solid diet . The exposure to the new environment and foreign antigens requires the establishment of appropriate defence responses . The neonate is immunocompetent, but the adaptive immune system is immature . Non-specific defence mechanisms, including the reactions of the acute phase response may thus be important for the adaptation to complicated physiological processes during growth and development of calves. Therefore, the concentrations of acute phase proteins may be influenced by the age of evaluated animals. The concentrations measured in young calves thus may differ from the values in adult cattle. Therefore, higher concentrations of acute phase proteins, which in adult cattle may indicate an inflammatory process, in young calves are not necessarily a sign of the activation of the acute phase protein production by some inflammatory stimulus, or a sign of a disease.
Possible factors affecting the concentrations of acute phase proteins after birth include foetal synthesis of acute phase proteins, the stimulation of their production by birth trauma, intake of colostrum containing acute phase proteins or their stimulants, and immaturity of synthesis capacity of the newborn liver . Introduction to the extrauterine environment, which contains various microbes, could also trigger an inflammatory response. Colostrum contains high amount of inflammatory mediators such as cytokines, which may induce the acute phase response in newborns. Transfer of colostral cytokines to the blood of calves has been reported by Yamanaka et al. . In addition, direct transfer of some acute phase proteins from colostrum to newborns may potentially occur. Schroedl et al.  found elevated concentrations of CRP in young calves. They concluded that although CRP in cattle is not a major acute phase protein, bovine colostrum contains high amounts of CRP and its transfer contributes to elevated concentrations in newborn calves. Moreover, high concentrations of mammary-associated SAA in the colostrum of healthy cows were found, which have a primarily protective effect on the gastrointestinal tract of neonates by stimulating mucin production and reducing adherence of pathogens . Immaturity of the neonatal liver to mount an acute phase response to an inflammatory stimulus could affect the concentrations of acute phase proteins in neonatal animals. For example, low Hp concentrations are common in newborn infants, which are related to the immaturity of the liver to produce Hp in a situation where Hp consumption is increased because of haemolysis of foetal erythrocytes .
Tóthová et al.  evaluated the age-dependent changes in the concentrations of haptoglobin (Hp), serum amyloid A (SAA) and fibrinogen (Fbg) in clinically healthy calves during the first 6 month of life. The most pronounced changes they observed in the concentrations of SAA, with the highest concentrations at the age of 1 month followed by gradually decreasing values to 5th month of life (Table 1). Orro et al.  reported also higher mean serum concentrations of SAA shortly after birth, being the highest at the age of 7 days (112.0 mg/l), and decreased after 10 days of age. In contrast, low SAA concentrations have been noted by Alsemgeest et al.  in calves sampled within 10 min after parturition. The results obtained by Tóthová et al.  showed in calves less pronounced changes in the Hp concentrations during the first three months of life than those observed in the serum SAA concentrations. The concentrations of Hp in the blood serum of calves in the first three months after birth were roughly uniform, and the values were comparable with the concentrations measured in healthy adult cattle. Similar findings were reported by Hyvönen et al
5. Acute phase proteins in cattle
Haptoglobin (Hp) is a glycoprotein composed of 2 α and 2 β subunits. The α subunit has a molecular weight of 16 – 23 kDa and the β subunit 35 – 40 kDa. The subunits combine in the form of a β-α-α-β tetramer chain . In the circulation, Hp is highly polymerized having a molecular weight of approximately 1000 – 2000 kDa, and exists also as polymer associated with albumin . The primary function of Hp is to bind free hemoglobin in the blood. By removing from the circulation any free hemoglobin, which has inherent peroxidase activity, Hp prevents oxidative damage to tissues . The Hp-hemoglobin binding also reduces the availability of the heme residue from bacterial growth and therefore Hp has an indirect anti-bacterial activity . Many studies have indicated the significance of Hp as a clinically useful parameter for measuring the occurrence and severity of inflammatory responses in cattle with mastitis, pneumonia, enteritis, peritonitis, endocarditis, abscesses, endometritis and other natural or experimental infectious conditions .
Assays for serum Hp concentration include spectrophotometric methods and immunoassays. The spectrophotometric assays are based on the ability of Hp to bind hemoglobin (Hb), forming Hp-Hb complexes that either alter the absorbance characteristic for Hb in proportion to the concentration of Hp in a serum sample, or preserve peroxidase activity at an acidic pH, which then can be detected and quantified . In addition, an automated spectrophotometric multispecies assay based on this reactivity has been developed . Nephelometric immunoassays, in which the rate of the precipitation of the antibody-antigen complex is measured, have been validated for the estimation of Hp .
5.2. Serum amyloid A
Serum amyloid A (SAA) is a small hydrophobic protein (9 – 14 kDa), which is found in serum associated with high density lipoprotein. In humans, four separate isoforms have been identified . Of these, SAA1 and SAA2 respond to an acute phase reaction with increased production from the liver. In contrast, SAA4 is a constitutive protein that is produced normally at low concentrations and is not affected by the acute phase response. The SAA3 isoform is expressed in non-hepatic tissues during the acute phase response with increases found in lung, adipose tissue, ovarian granulosa, as well as in the mammary gland . The mammary isoform (M-SAA3) has also been detected in bovine colostrum . Among the functions ascribed to SAA have been reverse transport of cholesterol from tissue to hepatocytes, opsonisation, inhibition of phagocyte oxidative burst and platelet activation . The M-SAA3 isoform found in colostrum stimulates the production of mucin from intestinal cells assisting the initiation of secretions from the neonatal intestine and helping to prevent bacterial colonization .
Enzyme linked immunosorbent assay (ELISA) is the commonest format for immunoassays of SAA. A cross species SAA immunoassay has been developed for measuring in veterinary medicine, that can be used in most species as the antibody shows species specificity for SAA . In addition, the latex agglutination test and turbidimetric immunoassay has been validated for SAA determination .
Fibrinogen (Fbg), a precursor of fibrin, is also an acute phase protein, which has been used for many years to evaluate inflammatory and traumatic diseases in cattle, and is characterized by markedly increased synthesis in response to infection . Fibrinogen is a β-globulin present in the plasma. It is composed of 3 polypeptide chains linked by disulfide bridges and a glycoprotein . Fibrinogen is involved in homeostasis, providing a substrate for fibrin formation, and in tissue repair, providing a matrix for the migration of inflammatory-related cells . Assays for fibrinogen have been largely dependent on its biological activity based on the rate of formation of insoluble fibrin in the presence of excess thrombin or on its precipitation following mild heat treatment .
Serum albumin is the major negative acute phase protein. During the acute phase response the demand for amino acids for synthesis of the positive acute phase proteins is markedly increased, which necessitates reprioritization of the hepatic protein synthesis: albumin synthesis is down-regulated and amino acids are shunted into synthesis of positive acute phase proteins . It has been reported that during the acute phase response 30 to 40 % of the hepatic protein synthesizing capacity is used for production of positive acute phase proteins and the production of other proteins thus need to be diminished . Albumin is responsible for about 75 % of the osmotic pressure of plasma and is a major source of amino acids that can be utilized by the animal's body when necessary. In routine practice, albumin is usually measured by spectrophotometric methods, such as the bromcresol green assay. However, overestimation of albumin can occur in heparinized plasma samples assayed by this method .
6. Acute phase proteins in pigs
In the pigs, C-reactive protein, haptoglobin, α1-acid glycoprotein, and pig specific major acute phase protein were identified as the diagnostically most important acute phase proteins.
6.1. C-reactive protein
In the pigs, as in the dogs and humans, C-reactive protein (CRP) is the prototypical acute phase protein with major diagnostic value. This protein was the first acute phase protein to be described. Originally named for its ability to bind the C-polysaccharide of
Measurement of serum CRP is generally by immunoassays using specific CRP antibodies, and several formats have been developed and described for this purpose, such as immunoturbidimetric assay, ELISA, or latex agglutination tests [60,61]. Currently, a commercial ELISA kit is available that is specific for porcine CRP, although technical improvements are needed to decrease between-run imprecision.
6.2. Alpha1-acid glycoprotein
The main biochemical characteristic of α1-acid glycoprotein (AGP) is that it is a highly glycosylated protein and is the main protein component in seromucoid . It does bind to a number of metabolites such as heparin, histamine and serotonin, steroids and catecholamines . AGP is also known to bind to pharmacological compounds which may have therapeutic implications as the amount bound can affect the metabolically active fraction of the drug. Increased AGP due to an acute phase response thus may reduce the concentration of free drugs, thus affecting their pharmacokinetics.
Although AGP can be estimated by precipitation of the majority of serum proteins by perchloric acid and quantification of the remaining soluble proteins, this protein is usually measured by single radial immunodiffusion on agarose gel impregnated with anti-species AGP rabbit serum . These tests are species-specific; however, they have the disadvantage of requiring 24 or 48 hours for diffusion to be complete.
6.3. Pig specific major acute phase protein
Specifically in the pigs, this specific acute phase protein (pig MAP) of unknown function has been reported to be a sensitive indicator of infection. Increases in pig MAP have been shown during infections with
7. Acute phase proteins in cattle diseases
7.1. Acute phase proteins in calves
7.1.1. Acute phase proteins in calves with respiratory diseases
Respiratory diseases are one of the leading causes of morbidity and mortality in calves and young cattle, and may account for serious economic losses . In case of dairy calf pneumonia, diagnosis and treatment are mainly based on the observation of clinical symptoms, such as depression and body temperature combined with specific disease signs. However, in many cases, the infected calves show only mild clinical symptoms that could be easily missed in a group of calves on a farm . To prevent disease outbreaks, early detection, isolation and treatment of diseased animals is important. Therefore, there is a need for objective parameters that are suitable as indicators of health or disease in calf herds applicable in the laboratory diagnosis of diseases. These proteins have been found to increase in the serum of cattle with many different diseases, including experimentally induced and naturally occurring respiratory tract diseases .
Respiratory-tract diseases are considered to be multi-factorial with causative agents, calf factors and environmental factors. The most common agents found in association with respiratory diseases are viruses such as bovine respiratory syncytial virus (BRSV), bovine herpesvirus (BHV-1), parainfluenza- virus (PI-3). On the other hand, secondary bacterial infections, e.g.
Godson et al.  investigated the serum protein profile from animals with bovine respiratory diseases to identify bovine acute phase proteins which may be used as indicators of the disease. For this reason, they experimentally reproduced bovine respiratory diseases, by challenging seronegative calves with bovine herpesvirus (BHV-1) on day 0 and
Heegaard et al.  evaluated the acute phase response of calves to experimental viral infection with bovine respiratory syncytial virus (BRSV). While the serum concentrations of both serum amyloid A and haptoglobin remained low in all control animals in this study, the SAA concentrations became elevated in the most of experimentally infected animals. This elevation was detectable at day 5 after infection, and peaked around day 5 – 8
||0.05 ± 0.06||1.11 ± 0.80||< 0.001|
||28.02 ± 20.60||63.19 ± 39.42||< 0.01|
According to Nikunen et al. , the use of different acute phase proteins as markers of naturally occuring respiratory diseases is somewhat controversial. In the study presented by these authors, only
||0.81 ± 0.60||1.56 ± 0.86||< 0.05|
||44.70 ± 30.78||90.07 ± 35.73||< 0.01|
Most of the investigations on the synthesis of acute phase proteins in animals with respiratory diseases have been focused on the immediate or acute phase response of the infection. However, only a few reports on the acute phase protein production in chronic inflammatory conditions have been published. Horadagoda et al.  found that the concentrations of Hp, SAA and α1-acid glycoprotein were higher in cases of acute compared with chronic inflammation. The results presented by Tóthová et al.  showed that not only acute diseases of the respiratory tract, but also chronic cases are characterized with increased production of some acute phase proteins, predominantly haptoglobin with concentrations in calves with chronic respiratory diseases more than twentyfold higher compared with healthy animals (Table 2). In addition, in the aforementioned study, cases with severe clinical signs and poor prognosis were associated with markedly higher Hp and SAA concentrations (Table 3). Thus, Hp concentrations in the range of 1 – 3 mg/ml, and SAA concentrations around 100 μg/ml predict severe course of the disease with poor prognosis. Similar findings were reported in calves by Heegaard et al. . Skinner et al.  found that Hp concentrations of more than 0.2 mg/ml indicate mild infection, values above 0.4 mg/ml suggest severe infection, while extended pathological conditions are typically associated with Hp values in the range of 1- 2 mg/ml. These results suggest the wide use and possible application of acute phase proteins to determine respiratory diseases and the magnitude of inflammatory changes in calves, choose proper therapy and monitor the efficiency of the treatment.
7.1.2. Acute phase proteins in calves with diarrhoea
Diarrhoea in calves, together with respiratory diseases, is another multifactorial disease entity that can have serious financial and animal welfare implications in both dairy and beef suckler herds. It has been estimated that 75 % of early calf mortality in dairy herds is caused by diarrhoea in the pre-weaning period . However, there are only few published data regarding the possible influence of diarrhoea on the concentrations of acute phase proteins and their usefulness in the diagnosis of these diseases. Piercy  investigated the production of ceruloplasmin in experimental infection with
The usefulness of the assessment of Hp, SAA and fibrinogen concentrations for the monitoring of treatment in calves having diarrhoea was evaluated by Jawor . In the aforementioned study, 40 % of calves with diarrhoea had Hp concentration > 0.1 mg/ml (ranging to 0.49 mg/ml). During the treatment, the serum concentrations of Hp decreased. A high percentage of diarrhoeic calves with higher Fbg concentrations (mean Fbg concentration of 7.28 g/l) were detected at the beginning of the treatment, while during the treatment a gradual decrease was noted. However, fibrinogen estimation required an additional determination of plasma proteins to distinguish between a relative increase in hemoconcentration and an absolute increase of Fbg concentration during inflammation . The concentrations of SAA were elevated during the entire treatment period for most of the diarrhoeic calves. The very high initial serum SAA concentrations and subsequent significant decrease of values during the treatment suggest that this acute phase protein may be very useful in calves with diarrhoea. Similarly, the results presented by Tóthová et al.  showed in 10 calves with clinical signs of diarrhoea higher mean SAA concentration compared with clinically healthy calves (Table 4). However, in Hp and Fbg concentrations they found no marked differences between healthy and diarrhoeic calves, and haptoglobin does not reach the concentrations seen in other disease conditions in cattle. Thus, these findings indicate that the disturbances in the homeostasis, inflammatory reactions of the organism, and tissue damage caused by diarrhoea did not evoke sufficient inflammatory response giving a more marked systemic increase in the concentrations of measured acute phase proteins. Similarly, according to Muller-Doblies et al. , Hp requires a stronger stimulation to induce an increase in serum concentrations.
7.1.3. Acute phase proteins in calves with omphalophlebitis and multisystemic diseases
Seeing that the inflammation of the navel, the tissue damage and other pathologic lesions in the associated structures may cause inflammatory reactions, Tóthová et al.  evaluated calves with omphalophlebitis to detect if this disease may affect the concentrations of major acute phase proteins. The results presented in this study showed in calves with clinical signs of omphalophlebitis, similarly to the calves with diarrhoea, more markedly higher mean concentration of SAA than in clinically healthy calves. In the concentrations of Hp and Fbg there were no marked differences between healthy and sick animals (Table 4). These findings might be a consequence of a different initiation of the production of various acute phase proteins, seeing that SAA is a more sensitive acute phase protein than Hp in cattle, with rapid increase in serum concentrations after the inflammatory stimulus . An opposite trend with more markedly higher mean concentrations of Hp and Fbg was observed by Tóthová et al.  in calves affected by multisystemic diseases (with more than one affected organ – navel, joints, digestive tract, respiratory system), while the mean SAA concentration obtained in this group was only slightly higher compared with clinically healthy calves. Similar findings were reported by Gänheim et al. , who found higher concentrations of Hp and fibrinogen in calves with diarrhoea at the same time as respiratory symptoms compared to those that had signs of only respiratory diseases or diarrhoea.
7.2. Acute phase proteins in dairy cows
7.2.1. Acute phase proteins in cows with mastitis
Despite world-wide efforts, mastitis has remained economically the most important disease in dairy cattle, and despite different mastitis control programs it is still the major challenge for the dairy industry . While clinical mastitis is often easy to detect, sub-clinical mastitis, on the other hand, is a larger problem for the dairy industry since this condition shows no visible changes in the udder or in the milk . Sub-clinical mastitis is frequently diagnosed by Californian Mastitis Test (CMT), which may suffer from a lack of reproducibility. In addition, up to now, the evaluation of somatic cell count (SCC) has remained as the gold standard for determining udder health. However, it is not sufficient enough in discriminating between the clinical and sub-clinical form of mastitis . Therefore, it is of great importance to investigate biomarkers that could be used for rapid detection of sub-clinical mastitis. One of the ways to identify cows with sub-clinical mastitis would be the measuring of the concentrations of acute phase proteins. The production and usefulness of acute phase proteins in cows with experimentally induced mastitis and mastitis under field conditions were investigated by several authors.
Conner et al.  evaluated the concentrations of haptoglobin, ceruloplasmin and α-1 antitrypsin in cows with summer mastitis (septic mastitis) and clinically healthy cows. In all cows with mastitis, they found elevated concentrations of Hp, whereas in healthy cows the Hp values were undetectable. Moreover, all cows with summer mastitis included into this study had significantly higher concentrations of ceruloplasmin and α-1 antitrypsin in comparison to cows without mastitis. Skinner et al.  concluded that Hp concentrations of 0.2 g/l and above in cows with mastitis may indicate early or mild infection, while values higher than 0.4 g/l indicate severe infection.
The usefulness of acute phase proteins in the diagnosis of mastitis was investigated by Hirvonen et al.  in pregnant heifers experimentally infected with
The hypothesis that the major acute phase proteins in cows may be transferred into milk during the acute phase response caused by mastitis was investigated by adapting the assays to measure the concentrations of proteins in milk. Eckersall et al.  reported also that the most of serum proteins leak into milk across the blood-mammary barrier as a result of the disruption caused by the inflammation due to mastitis. Moreover, milk seems to be a better sample material than serum for testing the concentrations of acute phase proteins during mastitis (easier and quicker sample collection without stressing the animals). The potential value of measuring the concentrations of acute phase proteins in milk as a means of detecting mastitis in cows was assessed by Eckersall et al. . According to their results, the milk samples from cows with both mild and moderate mastitis had significantly higher Hp, as well as SAA concentrations than the milk from healthy cows. Moreover, in milk samples from cows with moderate mastitis, the SAA concentrations were significantly higher than in cows with mild mastitis. On the other hand, in the milk Hp concentrations there were no significant differences between the infected cows. Thus, the milk SAA concentrations seem to have a greater potential for the detection of the severity of mastitis, since it has higher sensitivity and specificity in differentiating cows with mastitis .
The SAA response in milk and plasma to experimental intramammary inoculation of
Grönlund et al.  examined the concentrations of Hp and SAA in cows with naturally occuring chronic sub-clinical mastitis. The comparison of acute phase protein concentrations in quarter and composite milk samples was made also in this study. Almost all quarter milk samples from healthy control cows had undetectable concentrations of Hp and SAA. In cows with chronic sub-clinical mastitis, increased concentrations of both measured acute phase proteins in milk were observed, indicating an activation of the acute phase response also in cows with chronic mastitis, but the contents of Hp and SAA varied markedly. Haptoglobin and SAA were detected by the aforementioned authors in 83 % of the examined composite milk samples. Thus, according to Grönlund et al. , since cows had to have detectable concentrations of Hp or SAA in at least two udder quarters for elevated values to be found in the composite samples, analysis at the quarter level is preferable.
Further investigations showed an extrahepatic synthesis of specific isoform of serum amyloid A directly from mammary epithelial cells (M-SAA) . Therefore, M-SAA is believed to be more sensitive indicator of mastitis, which accumulates in milk only during mammary inflammation. The usefulness of M-SAA in the diagnosis of clinical and sub-clinical mastitis in cows with various clinical findings on the mammary gland was investigated by Kováč et al. . Their results showed markedly higher M-SAA concentrations in milk samples from quarters with clinical changes, as well as from quarters without clinical signs of mastitis, but with strongly positive Californian Mastitis Test (Table 5). In addition, the concentrations of M-SAA found in samples from mammary quarters without clinical changes were also relatively high (mean value of 473.7 ng/ml), as the uninfected mammary quarters had to have very low or undetectable concentrations of M-SAA. These results suggest that some quarters might be affected by inflammatory process, but still without positive reaction of CMT. Elevated concentrations of M-SAA in quarters with mastitis compared to healthy quarters were reported also by Petersen et al.  and Nazifi et al. .
|I. (n=7)||II. (n=12)||III. (n=13)||IV. (n=9)|
The response characterized by increased synthesis of M-SAA is specific for the quarter and does not necessarily result in detectable concentrations in composite milk samples. The results presented by Kováč et al.  showed similar trend of changes in the concentrations of M-SAA in composite milk samples and in samples from separate quarters, but the values measured were lower in composite milk samples, which suggest a diluting effect of milk from quarters with less marked changes (Table 5). Grönlund et al.  reported also some interpretative problems by the use of composite milk samples if only one quarter is sub-clinically infected. Therefore, it seems that composite milk samples are less suitable for detection of sub-clinical mastitis than samples from separate mammary quarters. In addition, the results presented by Kováč et al.  showed in cows with clinical mastitis higher concentrations of Hp and SAA in blood serum (Table 5), which suggest that localized severe inflammation of the udder is sufficiently intense to induce a measurable systemic acute phase response. However, the finding that the differences in serum Hp and SAA concentrations observed between the groups of cows with various clinical findings on the mammary gland were less significant than the differences in M-SAA concentrations means that the measuring of serum concentrations of some acute phase proteins would be less useful to the evaluation of the severity of mastitis than the measuring of the concentrations of M-SAA directly in milk samples.
7.2.2. Acute phase proteins in cows after parturition and cows with peripartum reproductive disorders
The period after parturition is the most critical period in dairy cows regarding health status and production. Factors such as pregnancy, parturition, blood calcium concentrations, initiation of lactation and feed intake all affect the ability of the cow’s immune system to effectively combat infections. The periparturient period is the time where these complex physiological changes occur simultaneously, having a significant effect on the animal’s health . Parturition, changes in homeostasis, metabolic and physiological challenges occuring in this stressful period, as well as other external and internal harmful stimuli may contribute to the activation of host immune system and inflammatory responses, including the initiation of the production of acute phase proteins. Major bovine acute phase proteins, haptoglobin and serum amyloid A, play an important role also in the reproductive processes, they intensify the phagocytosis process against the pathogens introduced into the uterus, and help by the reconstruction of the endometrium .
Saini et al.  reported that lactation and pregnancy in cattle appeared to have no effect on the Hp concentration in blood serum. However, according to Gymnich et al.  haptoglobin concentrations undergo significant changes around parturition, and in horses and cows the highest concentrations were observed 1 day post partum. Uchida et al.  evaluated the concentration of Hp in cows in the periparturient period and they observed significantly higher values around parturition than before and after parturition. Similarly, Ametaj  and Tóthová et al.  reported in cows after parturition an increase of two main acute phase proteins, Hp and SAA. According to the results presented by Chan et al. , the SAA concentrations in healthy cows reached the highest values within 3 days after the delivery (mean value of 66 mg/l). The Hp concentrations in the most of the evaluated animals were higher than 130.9 mg/l within 3 days after calving. Parturition with following metabolic challenges constitutes a potentially stressful event for the dairy cow. One of the ways how an animal can manifest stress is in the form of activated acute phase response, including the increased production of acute phase proteins by the liver. According to Alsemgeest et al. , the physiological processes taking place around the time of parturition are mainly responsible for higher concentrations of acute phase proteins in blood serum. Regassa and Noakes  reported that higher values of acute phase proteins could be related to the tissue damage occuring due to the increased myometrial activity during expulsion of the calf, involution of the uterus, as well as degeneration and regeneration of the endometrium. Young et al.  found that higher concentrations of these proteins, determined in the last phase of pregnancy and after calving may be connected with the changing hormone profile (the influence of estrogens and progesterone). In addition, it is worth pointing out that the increase in acute phase protein concentrations in cattle may be caused also by the increased concentrations of cortisol .
Postpartum endometritis is a common problem in cattle, because uterine contamination following calving is frequent, but most cows are able to eliminate bacteria from the uterus within 2 to 3 weeks after calving without manifesting marked clinical signs of the disease. However, cows that can not eliminate the infection may subsequently develop endometritis. Skinner et al.  reported that Hp concentrations are high in cows with metritis, with mean serum Hp concentration in cows with severe metritis of 1.04 g/l. Chan et al.  evaluated clinically healthy cows and cows with postpartum reproductive diseases after calving, and the Hp concentrations in clinically diseased cows (1133.5 mg/l) were significantly higher than in clinically healthy cows (104.6 mg/l). In a later study presented by Chan et al. , cows with acute puerperal metritis had significantly higher Hp concentrations than those in healthy cows throughout the 6 months after delivery. The highest Hp concentration was found in the period of 3 days after parturition (1.1 g/l), and for SAA concentrations 4 – 7 days
The usefulness of acute phase proteins by the evaluation of the efficiency of therapy was investigated by Mordak  in cows with retained placenta (with or without manual removal of the membrane). The highest Hp concentration they found in cows where the placenta had been expelled after 4 days (2.22 g/l), and the lowest in cows where the placenta had been easily removed manually (0.9 g/l).
7.2.3. Acute phase proteins in cows with hoof diseases and lameness
Bovine lameness and hoof diseases represent one of the major health problems for the dairy industry, and raise important questions about economic aspects and welfare issues in agriculture . Economic losses arise from decreased milk production, poor performance, fertility problems, increasing culling rates and treatment costs. The predominant hoof problems causing lameness in cows are sole ulcers, white line abscesses, interdigital phlegmons and digital dermatitis . Disorders in the locomotory system (due to damaged tissues, painfull processes, impaired homeostasis) may lead to a systemic acute phase response characterized by higher concentrations of some acute phase proteins. Therefore, some acute phase proteins may be useful in the early detection of lame cows in order to limit the losses related to lameness.
||0.094 ± 0.086||0.450 ± 0.601||< 0.05|
||12.70 ± 16.80||113.90 ± 55.66||< 0.001|
||2.19 ± 0.37||2.95 ± 0.65||< 0.001|
The usefulness of acute phase proteins in the detection of lame cows was evaluated by Kujala et al. . They investigated the acute phase response, including the concentrations of Hp and SAA in cows with sole ulcers and white line diseases. Their results showed higher concentrations of SAA in lame cows than in healthy animals, with values elevated from day 0 until days 7 – 8. The SAA concentrations started to decrease on day 14. In the serum Hp concentrations, no significant differences between healthy and lame cows were found. Significantly higher concentrations of Hp, SAA, as well as fibrinogen were found by Tóthová et al.  in heifers with hoof diseases (including pododermatitis, laminitis, sole ulcer, and digital dermatitis) compared to healthy animals (Table 6). Laven et al.  evaluated the concentrations of Hp, Fbg, ceruloplasmin and seromucoid in first lactation heifers with hoof horn haemoorhagies to determine the relationships with the development of the disease. However, they found any relationships between the presence of acute phase response and the development of hoof horn haemorrhagies in heifers after calving.
The presence of acute phase response in association with lameness due to claw disorders was investigated by Smith et al.  in dairy cattle on a commercial farm. In addition, they evaluated the effect of treatment on the acute phase protein concentrations and thus measured the effectiveness of the treatment. Into the evaluation they included cows diagnosed with pododermatitis septica, pododermatitis circumscripta, interdigital necrobacillosis and papillomatosis, digital dermatitis, as well healthy cows as control animals. The concentrations of serum Hp of all healthy cows without lameness were undetectable. Lame cows with any of the presented claw disorders were found to have increased serum Hp concentrations. In animals with pododermatitis septica and interdigital necrobacillosis, the Hp concentrations decreased after the treatment between days 1 to 5, which indicated effective treatment for these disorders. In contrast, treatment did not affect the concentrations of Hp in animals with pododermatitis circumscripta. Jawor et al.  evaluated the concentrations of acute phase proteins at selected time points during the treatment of cows with limb diseases with an aid to monitor the treatment and as an early predivtive marker of possible complications. In the examined cows, arthritis, sole ulcer, and white line disease were the most often diagnosed diseases. The highest concentrations of Hp, SAA and Fbg were recorded at the beginning of the treatment. In the cows, in which the treatment process went without complications, a high gradual decrease of acute phase protein concentrations was observed. This proved that the treatment applied was appropriate and that it contributed towards reducing the inflammatory process in cows. In cows with further complications (e.g. wound infections, bronchitis, the occurence of other inflammatory states of the limbs), they found increases in one or two of the measured acute phase proteins at the next blood collection. This indicates that these cows had not completely recovered and the treatment should be continued.
7.2.4. Acute phase proteins in cows with abdominal disorders
The usefulness of the measurement of acute phase protein concentrations in cattle, predominantly of fibrinogen, has been described in traumatic pericarditis, reticuloperitonitis, abomasal displacement, and by the monitoring of postoperative complications, as well as by the differentiation of reticuloperitonitis from other gastrointestinal disorders [51,129]. Very high plasma Fbg concentrations were reported by McSherry et al.  in cows with pericarditis and peritonitis.
After abdominal surgery, the condition of the patient is usually followed-up by physical observation. As complications are frequent, a more accurate indicator of their occurrence and severity would be valuable. Therefore, Hirvonen and Pyörälä  evaluated the usefulness of Fbg and Hp in the diagnosis of traumatic reticuloperitonitis in dairy cows. In addition, they studied how abdominal surgery affects these parameters, and whether they can be used to predict recovery from abdominal disorders. In this study, the preoperative Fbg and Hp concentrations in cows with traumatic reticuloperitonitis were significantly higher than those for cows with abomasal displacement or explorative laparotomy. The plasma Fbg values in cows with traumatic reticuloperitonitis remained high for about 2 days after surgery. The Hp concentrations in these cows showed only a small increase, which was followed by a steady decrease during the late hospitalization phase. However, the concentrations of both Fbg and Hp remained above normal values at the time of hospital discharge. Moreover, the values measured correlated well with the clinical findings from those cows with traumatic reticuloperitonitis. Thus, Hirvonen and Pyörälä  concluded that these proteins may be attractive parameters for the evaluation in the diagnostic of traumatic reticuloperitonitis.
According to McSherry et al. , displacement of the abomasum does not usually induce a significant fibrinogen response. In the study presented by Jawor et al.  the Fbg concentrations in cows with displaced abomasum were within normal values. Significant changes during the post-operative monitoring were found only for SAA concentrations. Nazifi et al.  evaluated the possible relationships between cardiac diseases (functional murmurs, pathologic murmurs, endocarditis, and pericarditis) and the concentrations of acute phase proteins in dairy cattle. In this study, cases with pericarditis and endocarditis had higher Hp and SAA concentrations than the cows with functional and pathological murmurs. In addition, the concentrations of the both measured acute phase proteins were lower in cows with endocarditis than those measured in cows with pericarditis, which suggest that the measurement of acute phase proteins can be helpful in differentiating an acute inflammatory condition like pericarditis from other cardiac disorders.
8. Acute phase proteins in swine diseases
Acute phase protein testing offers a tool for assessing a health status also in pig production systems. An important practical aspect in the pig production is the sub-clinical condition that does not lead to overt disease but may cause suboptimal growth and decreased welfare. A number of investigations indicate the ability of acute phase protein measurements to reveal such conditions [133,15]. In addition, lower gaining pigs were found to have higher acute phase protein levels than high gaining pigs .
Porcine C-reactive protein has been found to rise in experimental models of
The relationships between the serum concentrations of acute phase proteins and the appearance and severity of lesions in pigs at slaughter was evaluated by Pallarés et al. . They determined whether the concentrations of acute phase proteins could be used as markers for the presence of lesions and as a tool to detect sub-clinical disease in fattening pigs. In the aforementioned study, the concentrations of CRP in pigs with clinical signs of diseases and poor body condition were significantly higher than in apparently healthy pigs with gross lesions at slaughter (about 2.1 fold higher) and in apparently healthy pigs without gross lesions at slaghter (about 2.6 higher). Moreover, they found significant differences between apparently healthy pigs with marked lesions and without marked lesions at slaughter. Similar findings were recorded also in the serum Hp concentrations. For the concentrations of SAA, although the values recorded in pigs with clinical diseases were significantly higher than in apparently healthy pigs, the differences between pigs with gross lesions and without gross lesions were not significant. In addition, the serum CRP concentrations were significantly higher in pigs showing lesions in the lungs and one or more other organs compared to pigs showing lesions only in the lungs. Thus, the results presented by Pallarés et al.  indicate that the serum concentrations of CRP, SAA, as well as Hp can be used as markers of clinical diseases in pigs. These findings agree with those of Chen et al. , in which serum Hp and CRP concentrations were significantly higher in culled pigs than in clinically healthy pigs. However, according to Pallarés et al. , only Hp and CRP could be used as markers of the presence of lesions at slaughter, since they appear to differentiate apparently healthy pigs with lesions from pigs with no lesions. The presence of elevated serum Hp and CRP concentrations in apparently healthy pigs at slaughter could provide important information to a veterinary inspector about the presence of sub-clinical lesions that could lead to condemnations or a decrease in the quality of carcasses.
The objective determination of animal health is important due to the increasing focus of consumers and farmers on the welfare of animals. As non-specific markers of inflammation, acute phase protein testing is a useful tool for the assessment of health in general, to monitor the health state, the spread of infection or the efficacy of treatment. The measurement of acute phase proteins may also be useful in defining the objective health status of an animal or a herd. They are reliable biomarkers that can be used both in diagnostic approaches and for research purposes.
Practical uses and advantages of acute phase protein assays have been described in a large number of scientific reports published in the last few years. Clinical application of acute phase proteins has not been extensive in routine clinical animal practice due to practical limitations associated with their analysis. The most of the methods available for measuring specific acute phase proteins are immunological methods, which are time-consuming and relatively expensive, so limiting the wide-scale use of acute phase proteins in routine practice. Seeing that there is a broad spectrum of possible applications of acute phase protein based diagnostics for the use in ruminants and swine, it is necessary to develop and optimise rapid field tests that allow the determination of acute phase proteins in a short time period.
Despite the challenges in the determination of acute phase proteins, with the insights provided by ongoing research in this area, it is likely that these analytes will be increasingly used in the diagnosis and prognosis of diseases also in farm animal medicine. Acute phase proteins have proven to be very useful in the early detection of sub-clinical diseases or alterations of the health status of an animal, with predictive information regarding the development of disease. Changes in the serum concentrations of acute phase proteins indicate the need for a more detailed clinical evaluation of a patient. In addition, acute phase proteins can be a powerful tool in the monitoring of treatment.
AcknowledgmentsThis work was supported by VEGA Scientific Grants No 1/0592/12 and 1/0812/12 from the Ministry of Education, and by Slovak Research and Development Agency under contract No. APVV-0475-10.
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