Received: 1 July 2022 | Revised: 30 September 2022 | Accepted: 8 November 2022 DOI: 10.1111/vcp.13220 REVIEW ARTICLE Acute phase proteins in cattle and swine: A review Yolanda Saco | Anna Bassols Departament de Bioquímica i Biologia Molecular, Servei de Bioquímica Clínica Abstract Veterinària, Universitat Autònoma de The major acute phase proteins (APPs) in cattle are haptoglobin (Hp) and serum am- Barcelona, Cerdanyola del Vallès, Spain yloid A (SAA), and in swine, are Hp, SAA, C-­reactive protein (CRP), and Pig major Correspondence acute phase protein (Pig-­MAP). Many methodologic assays are presently available to Anna Bassols, Facultat de Veterinària, Departament de Bioquímica i Biologia measure these parameters, which are still being improved to increase their specificity, Molecular, Servei de Bioquímica Clínica sensitivity, user-­friendliness, and economic availability. In cattle, the main applications Veterinària, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, are the diagnosis and monitoring of frequent diseases such as mastitis and metritis in Spain. dairy cows and respiratory problems in young calves. In pigs, APPs are useful in the Email: anna.bassols@uab.cat control of bacterial and viral infections, and they may be used at the slaughterhouse to monitor subclinical pathologies and improve food safety. The utility of APP in animal production must not be forgotten; optimization of protocols to improve performance, welfare, and nutrition may benefit from the use of APPs. Other sample types besides serum or plasma have potential uses; APP determination in milk is a powerful tool in the control of mastitis, saliva is a non-­invasive sample type, and meat juice is easily obtained at the slaughterhouse. Increasing our knowledge of reference intervals and the influence of variables such as age, breed, sex, and the season is important. Finally, worldwide harmonization and standardization of analytical procedures will help to expand the use of APPs. KEYWORDS acute phase response, C-­reactive protein, Haptoglobin, ITIH4, pig-­MAP, serum amyloid A 1 | M A I N ACU TE PH A S E PROTE I N S I N inflammatory pathologies, but they are cleared from the circulation C AT TLE A N D S W I N E within a few hours, whereas APP concentrations remain altered for a long time after the stimulus. Acute phase proteins (APPs) are produced by the liver upon stim- APPs are classified as positive (major, moderate, or minor) or ulation by pro-­ inflammatory cytokines, such as interleukins-­ 1β negative depending on if concentrations are increased or decreased and -­6 (IL-­1β and IL-­6) and tumor necrosis factor-­α (TNF-­α), in re- after a triggering event. There is a consensus as to which are the sponse to infection, inflammation, or trauma. These cytokines are most relevant APPs in cattle and swine (Table 1).1,2,5,6,9,14 The major thus used as biomarkers for these conditions in experimental and APPs are Haptoglobin (Hp) and Serum Amyloid A (SAA) in both cattle field studies, and many interesting reviews have been previously and pigs. C-­reactive protein and Pig major acute phase protein (Pig-­ published as a general topic1–­8 or about specific animal species.9–­13 MAP) are considered major APPs in pigs, and lipoprotein-­binding Pro-­ inflammatory cytokines may also be useful in monitoring protein (LBP) is a major APP in cattle.15 Recently, inter-­alpha-­trypsin This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2022 The Authors. Veterinary Clinical Pathology published by Wiley Periodicals LLC on behalf of American Society for Veterinary Clinical Pathology. 50 |  wileyonlinelibrary.com/journal/vcp Vet Clin Pathol. 2023;52(Suppl. 1):50–63. | 1939165x, 2023, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vcp.13220 by Readcube (Labtiva Inc.), Wiley Online Library on [09/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SACO and BASSOLS 51 TA B L E 1 Main positive (major, moderate, and minor) and negative APPs were identified in cattle and swine. Species Major Moderate Minor Negative Cattle Hp, SAA, LBP AGP, ITIH4, CRP Fb Albumin, Apo-­A1 Swine Pig-­MAP, Hp, SAA, CRP AGP Fb Albumin Apo-­A1 Abbreviations: AGP, Alpha-­1-­acid glycoprotein; Apo-­A1, apolipoprotein A1; APP, acute phase proteins; CRP, C-­reactive protein; Fb, Fibrinogen; Hp, Haptoglobin; ITIH4, Inter-­alpha-­trypsin inhibitor heavy chain 4; LBP, lipopolysaccharide-­binding protein; Pig-­MAP, Pig major acute phase protein; SAA, Serum Amyloid A. TA B L E 2 Analytical techniques for the determination of acute phase proteins in cattle and swine. Type of analysis APP Advantages Disadvantages Colorimetric Hp Simple, multispecies, basic equipment, Some interferences Calibration unstable easy to automatize ELISA Hp, CRP, Pig-­MAP, ITIH4, SAA, LBP Species-­specific Species-­specific Laborious High dilutions Immunoturbidimetric Hp, CRP, ITIH4, Pig-­MAP Species-­specific Species-­specific Easy to automatize No or low dilutions Good reproducibility Higher precision than ELISA Radial SAA, Hp, ITIH4 Species-­specific Species-­specific Immunodiffusion Manual (RID) Low number of samples Point of care SAA, CRP, Hp Species-­specific Species-­specific On-­site testing Hp, MAA also for milk Abbreviations: APP, acute phase proteins; CRP, C-­reactive protein; Hp, Haptoglobin; ITIH4, Inter-­alpha-­trypsin inhibitor heavy chain 4; LBP, lipopolysaccharide-­binding protein; Pig-­MAP, Pig major acute phase protein; SAA, Serum Amyloid A. inhibitor heavy chain 4 (ITIH4) has been identified as an APP in cat- immunoturbidimetry and ELISA. 22–­31 The availability of reagents and tle, which is the analog to porcine Pig-­MAP.16 assays easily adapted to biochemical analyzers will contribute to the incorporation of APP measurements into routine laboratory testing for monitoring large animal health and welfare. 2 | M A I N M E TH O D O LO G I C TEC H N I QU E S Likewise, the importance of having accurate reference intervals FO R A PP Q UA NTI FI C ATI O N I N S W I N E A N D (RIs) cannot be left aside. Calculation of RIs has to take into account C AT TLE the influence of variables such as age, sex, breed, and type of hous- ing. Published RI for calves and piglets demonstrate significant dif- An important requirement when determining APPs and other ana- ferences due to age.32–­35 lytical parameters in farm animals is that usually, a large number of samples have to be assayed, and automated techniques are advisa- ble (Table 2). More recently, other technologies and biosensors have 3 | M A I N A PPLI C ATI O N S O F A PP I N been adapted, but they are outside the scope of this review.17–­20 C AT TLE APPs have been studied in relation to many diseases in cattle and 2.1 | The importance of harmonization and dairy cows,14,36,37 but only select examples will be summarized here. adequate reference values Harmonization, namely, the preparation of reference materials for 3.1 | The transition period the calibration of reagents, is one of the most important require- ments needed to expand the use of APPs, and it is indispensable for In the dairy cow, the transition period is from the 3 weeks before the standardization of different methodologies and the dissemina- to 3 weeks after calving. This period is associated with a high inci- tion of knowledge to the field. 21,22 dence of pathologies, such as ketosis, mastitis, hypocalcemia (milk Several laboratories, including ourselves, have been involved fever), and reproductive problems. The risk of health problems in- in the preparation, optimization, and validation of assays based on creases during this time, and it is one of the main reasons for culling. | 1939165x, 2023, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vcp.13220 by Readcube (Labtiva Inc.), Wiley Online Library on [09/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 52 SACO and BASSOLS Proper management can significantly reduce the incidence of dis- (SCCs) has remained the gold standard for determining udder health. ease, meaning that the monitoring of the animals is required, and the However, APPs are useful as either a valuable complement or even determination of APP can help in achieving it. as an alternative to SCC. Normal calving induces an acute phase reaction on the days fol- In mastitis, there is a general increase in serum APP (Figure 1). lowing parturition.36,38,39 This indicates enhanced activation of the The most relevant are Hp,36 and SAA,53 although CRP, ITIH4, and immune system, even in cows with no clinical signs of metabolic LBP also have been identified.54 stress. In the presence of infection or exacerbated tissue injury, the response is more intense. In all cases, the objective of the inflam- matory response is to restore homeostasis and destroy pathogens. The best-­studied APP in this context has been Hp in high-­yielding dairy cows,40 cows consuming fresh pasture,41 and field studies per- formed at the farm level comparing different APP.42 SAA has also been used as an inflammatory marker in cows during peripartum43 and to assess the effect of nutritional management.44,45 3.2 | Metritis Metritis occurs when bacteria from the environment colonize the uterus during parturition. Incidence is high and costly, with 5% to 20% of cows experiencing metritis and, consequently, subfertility and infertility.46 As in other infectious diseases, APPs increase during metritis, and it has been proposed that this acute phase inflammatory response pre- cedes clinical metritis. In one study,47 cows were grouped into 3 health categories after calving (severe metritis, mild metritis, and healthy), and Hp concentrations were measured for several days prior to and after calving. Cows with mild and severe metritis had greater Hp concentra- tions than healthy cows, and, more importantly, increased Hp concen- trations preceded clinical signs of abnormal uterine discharge. Cows with Hp concentrations ≥1 g/L on day +3 after parturition were 6.7 times more likely to develop severe or mild metritis, and this predictive threshold had a sensitivity of 50% and specificity of 87%. Similar re- sults were obtained with Hp and SAA, which were associated not only with the short-­term development of metritis but also with chronic sub- clinical endometritis, other indicators of inflammation, and decreased reproductive performance.48,49 Recently, attention has been focused on SAA due to its rapid increase in plasma, its short half-­life, and the rapid dynamic of changes in blood concentration in metritis and other reproductive problems such as mastitis.50,51 The determination of CRP in uterine lavage fluid can be used as a local biomarker for evaluating uterine inflammation since it has been shown to decrease in parallel with the presence of leukocytes during uterine involution.52 In conclusion, APP screening may assist in the early detection of metritis, providing increased opportunities for early treatment and prevention. F I G U R E 1 Concentrations of (A) haptoglobin, (B) serum amyloid A, and (C) alpha-­1 acid glycoprotein (AGP) in serum from dairy cows 3.3 | Mastitis with mild or moderate clinical mastitis and healthy dairy cows. The plots show the median (line within the box), 25th and 75th Mastitis is recognized as one of the most important reasons for percentiles (box), 10th and 90th percentiles (whiskers), and outliers culling dairy cows. Up to now, the evaluation of somatic cell counts (dots). (From Eckersall et al., 200158; used with permission). | 1939165x, 2023, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vcp.13220 by Readcube (Labtiva Inc.), Wiley Online Library on [09/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SACO and BASSOLS 53 APPs can be measured in milk, which could be advantageous 3.4 | Respiratory and gastrointestinal problems compared with subjective or semiquantitative clinical criteria, such as palpation of the udder or evaluation of SCCs using cow-­side tests Respiratory and gastrointestinal problems are frequent in young (eg, California Mastitis Test). Synthesis of SAA and Hp occurs locally calves that are often subjected to husbandry conditions where in mammary epithelial cells, and this is the source of milk APPs. 55 The calves of different origins and health statuses are mixed, provision SAA isoform present in milk is SAA3 (or milk amyloid A, MAA), dif- of milk or solid feed is not always suitable, and prolonged transpor- ferent from the plasma isoform. The proteome of a mastitic cow has tation to rearing facilities occurs. At arrival, calves cannot consume been studied in serum and milk, and several differences have been the amount of milk and solid feed needed to cover nutritional re- identified.54,56 One is SAA, which does not correlate between the quirements, and the incidence of disease spikes. The most common 57 two sample types due to the presence of different isoforms. When disease is a bovine respiratory syndrome (BRD), aggravated by the several serum and milk APPs were measured in dairy cows, they stress suffered during transportation.71 The most common agents were found to have a similar diagnostic value to SCCs and proved to found in association with BRD are viruses such as bovine respira- have good sensitivity and specificity.58 Nevertheless, caution must tory syncytial virus (BRS), parainfluenza-­3 virus, adenovirus, and 59 be maintained when stored samples are used for analysis. bovine coronavirus. However, secondary bacterial infections are Colostrum contains APPs in large quantities; therefore, colos- common.72 In addition to welfare and economic problems, transport trum intake influences serum APP concentrations in calves. Maternal and commingling are one of the most important causes of antibiotic colostrum SAA and Hp have immunomodulatory roles and may have use in cattle. local protective effects in the gastrointestinal tract of neonatal dairy Measurement of Hp, LBP, and SAA have been studied as tools calves.60 for detecting BRD in feedlot conditions, and the combination of In healthy postparturient cows, APP concentrations in milk fall to high concentrations together with fever was found to be a very low levels within 4 days. Therefore, if APPs do not decrease (ie, ele- good indicator of disease.72–­76 SAA, LBP, and Hp are sensitive mark- vated APPs in milk after 4 days), they could be used as a biomarker of ers of respiratory infection, and they may be useful for exploring post-­parturient mastitis, allowing for an early intervention to reduce the host response to respiratory infections in clinical research.77,78 61 disease on dairy farms. Parity has been recognized as a possible Determination of APP at feedlot arrival may be useful in predicting confounding factor when diagnosing mastitis using milk Hp concen- subsequent performance and mortality rates of calves since high Hp trations since there is a positive correlation between Hp and par- concentrations inversely correlate with dry matter intake and body ity.62 Milk SAA3, Hp, and CRP differentiated samples from healthy weight.79 Furthermore, calves with elevated serum Hp concentra- quarters of cows with subclinical mastitis that do not show clinical tions had higher odds of being treated with antibiotics; thus, Hp signs of intramammary inflammation.62,63 In experimental studies, could be useful for making decisions regarding targeted prophylactic inflammatory cytokines (TNF-­α , IL-­1β, IL-­6, and IL-­10) and SAA3 in treatment.79 57,64 milk are correlated with one another and with clinical signs. In Hp concentrations may help predict lung consolidation and have another study, the kinetics of APP and cytokines in plasma and liver recently been validated as an accurate method for detecting BRD-­ biopsies were presented.65 Threshold concentrations for these pro- related lung pathology in dairy calves.80 Nevertheless, a systematic teins in milk that can be used to differentiate mastitic and healthy review of the diagnostic accuracy of Hp, SAA, and fibrinogen vs clin- udders have been recently published.66 ical reference standards for the diagnosis of BRD failed to confirm The agent of mastitis influences the clinical form of the disease, the utility of APP in the diagnosis of BRD.81 The authors pointed severity, and treatment. Investigating the secretion patterns of APP to the lack of standardization of procedures and clinical criteria to into milk may ultimately reflect the etiologic agent. The kinetics of explain this discrepancy.81 SAA in serum and milk in experimental mastitis induced by Escherichia coli,67 Pseudomonas aeuriginosa,68 and other pathogens63,64,69,70 were investigated. The highest concentrations of Hp were found in milk 3.5 | Performance, growth, nutrition, and stress in cases of mastitis caused by E. coli and Arcanobacterium pyogenes, and the lowest concentrations were in cases of mastitis caused by In large animals, there is an intense investigation of the acute phase coagulase-­negative staphylococci.69 The median concentration of response triggered by stress related to several conditions, such as SAA in milk was over 10 times higher in cases of mastitis caused by transport, feeding, or housing conditions. These studies are valuable 69 E. coli than in mastitis caused by other pathogens. Streptococcus for assessing the animal welfare status of the herds to both improve species are one of the most common etiologic agents of mastitis; the productivity and obtain products of higher quality. highest concentrations of SAA3 were found in the milk of cows with The effect of weaning, transportation, and commingling on the mastitis caused by S. agalactiae and S. uberis while SAA3 was lowest APP response has been studied, and Hp and SAA have been pro- in mastitis caused by S. dysgalactiae.70 In a field study performed in posed as the most sensitive APPs to monitor body weight increase to dairy farms in Scotland, Hp, SAA3, and CRP measured in milk pre- improve the management procedures of young calves.82–­84 sented similar profiles in mastitis caused by the same pathogen, and In our laboratory, we have studied how APP can reflect the over- there was a correlation with the clinical symptoms.63 all welfare status of cows living in different husbandry conditions. | 1939165x, 2023, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vcp.13220 by Readcube (Labtiva Inc.), Wiley Online Library on [09/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 54 SACO and BASSOLS We have analyzed the serum biochemical profile of Bruna dels vaccine since APPs have been observed to usually increase in cor- Pirineus and Alberes breeds living under different systems of hous- relation with antibody titers99 and with the intensity and duration ing and feeding, and SAA and Hp were increased in groups living in of clinical signs, as reported in vaccinated pigs prior to inoculation the mountains in winter.85,86 APP have been used to study immune with H. parasuis (the etiologic agent of Glässer's disease).98 However, system activation in nutritional studies, as in supplementation with the APP response is usually lower in vaccinated pigs compared with amino acids, where an increase in Hp, SAA, and LBP was observed those with natural infection, as was observed in a study on Lawsonia in cows administered L-­Glutamine.87 APP have been used to monitor intracellularis vaccination.100 Taking into account these consider- the potential inflammatory consequences of a grain-­rich diet, which ations, APPs could be used as biomarkers to help choose a vacci- can contain endotoxin, resulting in increased plasma concentrations nation protocol that minimizes inflammation, as was proposed in a 88 of Hp and SAA. study of pigs with Mycoplasma hyopneumoniae.101 Determining CRP concentrations in serum could be relevant for assessing impaired animal welfare in farrow-­ to-­ wean, nurs- 4 | M A I N A PPLI C ATI O N S O F A PP I N ery/feeder, and finishing pigs. Swine Inflammation and Necrosis SWINE Syndrome (SINS) is a newly identified clinical syndrome in which the translocation of intestinal bacterial products (eg, lipopolysaccha- In pigs, acute inflammation has been induced in non-­infectious ex- ride [LPS]) into the bloodstream is hypothesized to be responsible perimental models using the subcutaneous application of turpen- for the development of inflammation and necrosis in the extrem- 89 tine. The acute phase response has been characterized in this ities.102 Increased CRP concentrations have been detected in pigs species, and the major APPs have been defined as Hp, CRP, and affected by SINS due to inflammation and necrosis of the skin, tail, Pig-­MAP.90 and ears.103 A large number of experimental studies have been published in pigs with bacterial or viral infections. In addition to diagnostic, prog- nostic, and etiopathogenesis studies examining APPs, these proteins 4.2 | Viral infections have also been used in experimental studies as tools for the evalua- tion of antimicrobial and anti-­inflammatory agents and vaccines. In The APP response in viral diseases is more heterogeneous and de- farm control programs aimed at improving the quality of pig produc- pends on if an innate response to the virus is stimulated. Two dis- tion, some studies have supported the idea that analyzing Pig-­MAP eases that currently cause a significant economic impact on pig in one sub-­sample of a group of pigs might be a useful tool in routine farms are porcine reproductive and respiratory syndrome (PRRS) health and welfare monitoring.91 and post-­weaning multisystemic wasting syndrome (PMWS), caused In natural infections, APPs generally have a greater response in by the PRRS virus (PRRSV) and porcine circovirus type 2 (PCV2), animals that present with clinical signs, and the responses are usually respectively. of greater magnitude in bacterial infections or concurrent viral and PRRSV is characterized by a weak innate immune response with bacterial infections.92 Conversely, in clinical studies, such as surgical low production of pro-­inflammatory cytokines and, especially, with protocols, APPs have been measured in pigs as an animal model to very low production of interferon-­gamma (IFN-­γ). Therefore, an ef- assess inflammation.93 ficient acute phase response is not induced.14,104 CRP and Hp are the most sensitive APPs,105,106 but concentration variabilities have been reported, probably due to different viral strains or specific aspects 4.1 | Bacterial infections of the experimental design.106–­109 The importance of viral strain is clearly demonstrated in our analysis of the response to several In experimental infections, plasma concentrations of Hp and Pig-­ PRRSV isolates that produced different clinical outcomes; the APP MAP increased rapidly and remained elevated for 10–­15 days, response (Hp, CRP, and to a lesser degree, Pig-­MAP) was hetero- whereas CRP and SAA show very rapid increases (peaking at geneous and dependent on viral strain but also correlated with the 1–­2 days post-­infection) that decline to normal rapidly (4–­5 days severity of clinical signs (Figure 2).110 post-­infection). The kinetics of APP responses have been analyzed In PCV2-­infected animals, Hp and CRP have been found to cor- in experimental infections with Streptococcus suis, Actinobacillus relate with PCV2 viremia, and the clinical course of the disease,111 pleuropneumoniae,94–­96 Yersinia enterocolitica, Pasteurella multocida,97 but differences in the kinetics are reported depending on the exper- and Haemophilus parasuis.98 The concentration of APPs correlates imental infection protocol.112 with the severity of clinical signs, and in some cases, increases are Swine influenza virus (SIV) is one of the main etiologic agents detected before specific antibodies are increased against the bacte- that produce respiratory disease in pigs. Experimental studies de- ria.94 APPs have been measured to evaluate the efficacy of antimi- signed to evaluate the acute phase response have demonstrated in- crobials against A. pleuropneumoniae.95 creases in serum CRP, SAA, and Hp concentrations,113 with Pig-­MAP A number of studies have explored the potential for measur- being less sensitive.114 The increase in all of these APPs correlated ing APP concentrations to assess the protective efficacy of a given to the severity of clinical signs and lung lesions and was able to | 1939165x, 2023, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vcp.13220 by Readcube (Labtiva Inc.), Wiley Online Library on [09/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SACO and BASSOLS 55 F I G U R E 2 Serum concentrations of haptoglobin (mg/mL), C-­reactive protein (CRP μg/mL), and Pig major acute phase protein (Pig-­MAP mg/mL) in pigs inoculated with several strains of Porcine Respiratory and Reproductive Virus (PRRSV). Mean and S.E.M. for n = 5 pigs in each group are shown. *P < 0.05, **P < 0.01, ***p < 0.001 vs t = 0. (From Saco et al., 2016,110 used with permission). differentiate subclinical cases,115 although SAA has been proposed a significant increase in plasma SAA, CRP, and Hp concentrations as the best indicator for this pathogen.116 Coinfection with more in experimental ASFV and CSFV infections, with the increase in the than one pathogen has been described for SIV and H. parasuis,117 SIV plasma SAA concentrations being the most pronounced, and APP and P. multocida,116 and SIV and A. pleuropneumoniae.118 In general, concentrations quickly returning to normal concentrations.120 increases in APP correlated with the severity of the clinical signs and It is also important to emphasize that determination of APP con- were more severe than in single-­pathogen infections. centration, together with cytokines, is not only useful for diagnostic In infections caused by the African swine fever virus (ASFV), or monitoring purposes but also for the further study of viral disease Aujeszky's disease virus (ADV), or classical swine fever virus (CSFV), pathogenesis.121,122 different response patterns were observed. In general, the in- As with vaccines against bacterial infections, APPs can be used crease in plasma Hp, SAA, and Pig-­MAP concentrations are greater as biomarkers in nonclinical vaccine safety studies and can help than that of CRP for these three viruses, and APP concentrations identify a vaccination protocol that produces the lowest inflamma- evolved in parallel with viremia levels.119 Another study described tory reaction with the most effective protection in an individual. The | 1939165x, 2023, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vcp.13220 by Readcube (Labtiva Inc.), Wiley Online Library on [09/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 56 SACO and BASSOLS increase in APPs correlates with clinical signs, and our own results consolidation than in pigs with respiratory symptoms associated indicate that a vaccine against PCV2, which causes only a very mild with the porcine respiratory disease complex (PRDC), while the lat- and transient increase in rectal temperature did not induce an in- ter is characterized by significantly higher Hp concentrations.129 123 crease in Hp. Some studies have been performed in the field with the ob- jective of assessing whether the extrapolation of APPs from one pig sub-­group might be a useful tool in routine health and welfare 4.3 | Parasites monitoring programs aimed at improving the quality of global pig production. Using an immunochromatographic method to measure The APP response in response to parasites is heterogeneous. In Pig-­MAP on pig farms, the analysis of a sub-­sample of the pig pop- experimental infections with three species of Trichinella, increased ulation was found to be enough to detect diseases or stress condi- plasma Pig-­MAP, CRP, and Hp concentrations were mild and transi- tions that cause significant elevations in Pig-­MAP.91 tory, and none of these proteins was increased in any of the experi- mental groups of pigs at the same time point after infection.124 4.7 | Acute phase proteins as indicators of zootechnical performance 4.4 | Gastrointestinal diseases APPs have been proposed as biomarkers to assess growth perfor- More recently, we analyzed whether Pig-­MAP correlated with the mance since there is an inverse correlation between serum APP con- gold-­standard measure for intestinal wall integrity, which included centrations and production parameters. This study reasoned that the villi-­to-­crypt ratio (V:C ratio) and the measurement of other in- stimulation of the immune system and increased inflammation are flammatory markers (TNF-­α) and mucosa integrity markers (serum accompanied by reduced growth performance due to anorexia, as intestinal fatty acid protein, i-­FABP), in pigs with experimental infec- well as the partitioning of nutrients away from growth to support tions with Salmonella Typhimurium and the pathogenic E. coli strain, the immune system.130 An inverse relationship between serum APP ETEC K88. Our results showed that Pig-­MAP and TNF-­α inversely concentrations and production parameters would be anticipated. correlated with the V:C ratio.125 In 1992, it was proposed that the determination of serum Hp concentrations in pigs at 7 weeks of age could be an indicator of fu- ture weight gain.131 Similar results were described in 24-­week-­old 4.5 | Other pathologies animals132 and animals in the post-­weaning period.133 Thus, Hp was suggested as a surrogate marker for reduced pig growth in a study APPs have been investigated as markers for lactation problems in comparing several nursery feeding programs in pigs raised on com- sows. Due to complex etiopathogenesis, early diagnosis of postpar- mercial farms.134 In our laboratory, serum Hp concentrations were tum dysgalactia syndrome (PDS) is challenging and usually based on negatively correlated with improved production parameters (aver- the physical examination performed in the first days after farrow- age daily weight gain) throughout the growing and fattening periods ing. Determination of APPs, especially SAA, has been suggested as of the pigs.123 More recently, it has been proposed that alpha1-­acid an early marker of lactation impairment in sows, allowing for a high glycoprotein (AGP) could be used as an indicator of growth potential probability of detecting sows susceptible to lactation disorders.126 in newborn pigs,135 which may be surprising since AGP is a negative APP in pigs.136 Newborn runt piglets have higher AGP concentra- tions than piglets born with normal body weights; this may be the 4.6 | Acute phase proteins under field conditions main reason why AGP is considered a marker of growth. Body weight is a potent predictor of preweaning and post-­weaning growth, and In natural infections, the APP response is generally greater in ani- smaller pigs at birth grow slower. mals with clinical signs and concurrent viral and bacterial infections APPs may be useful as non-­ specific biomarkers to detect if than in those with no clinical signs or with infections with only one husbandry conditions, for example, the influence of suboptimal pathogen. An APP response of greater magnitude is described in outdoor climates at critical phases of life, will result in production bacterial diseases (M. hyopneumoniae) compared with that observed disturbances.137 in pigs affected by PRRS or ADV.92 Pig-­MAP and Hp concentrations are significantly increased in PMWS-­affected animals, even before the appearance of clinical signs.111,127 Increases in Hp and CRP con- 4.8 | Acute phase proteins in nutritional studies centrations are greater in pigs with PRRS that have a concomitant infection with M. hyopneumoniae.128 Sub-­therapeutic antibiotic doses have been used to prevent infec- Some authors propose to measure APPs as a tool for the differ- tious diseases, improve performance, and reduce medication costs ential diagnosis of diseases that cause emaciation in fattening pigs. In in pigs. However, due to the association of sub-­therapeutic antibiotic fact, higher CRP concentrations are observed in pigs with pulmonary dosing in feed with the increasing emergence of antibiotic-­resistant | 1939165x, 2023, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vcp.13220 by Readcube (Labtiva Inc.), Wiley Online Library on [09/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SACO and BASSOLS 57 bacteria, the use of antibiotics as feed additives has been banned concentrations have also been described in animals without clinical in the European Union (Regulation [EU] 2019/61 on Veterinary symptoms but with pulmonary lesions.147 A study of 24 farms pre-­ Medicines and Regulation (EU) 2019/4 on Medicated Feed). screened for the presence of either CVPC or pleuritis indicated that Alternatives to the use of antibiotics are urgently needed, and APP Pig-­MAP and possibly Hp are potential markers for characterizing and measurements may be helpful in monitoring the effectiveness of al- discriminating respiratory lesions at slaughter.148 Using a point-­of-­ ternatives. In this context, APPs have been used to assess the status care assay, Pig-­MAP concentrations from blood samples obtained at of the immune system in studies examining the efficacy of probiot- slaughter were increased in association with lesions found on carcass ics and immunomodulators as better alternatives to antibiotic feed inspection,91 suggesting that this may be useful for real-­time evalu- 138–­140 additives. ation. An extended study indicated that APPs could also be valuable Likewise, serum Hp has been used to evaluate the effects on the as predictive indicators for risk assessment in meat inspection, as in- immune status in studies examining supplementation with amino creased Hp and Pig-­MAP concentrations in slaughter blood indicated acids during disease challenge141 and diets supplemented with es- a 16-­and 10-­fold higher risk for organ abnormalities, respectively.149 142 sential amino acids. 4.10 | Acute phase proteins response in 4.9 | Acute phase proteins in slaughterhouse pigs stressful situations as health status markers Swine species are generally exposed to stressful environmental con- APPs have been used as a complement to ante-­mortem and post-­ ditions that can affect the immune response and increase the risk mortem inspection of swine. On arrival at the slaughterhouse, APPs of disease. Transportation, social stress, heat, and dietary changes could offer information on herd health on the farms from which are some of the main causes that produce stress.150 In response to the pigs originate and aid in detecting chronic disease in apparently stress, the hypothalamic–­pituitary–­adrenal (HPA) axis is activated, asymptomatic animals. One study found that Hp concentration in stimulating glucocorticoid production in the adrenal gland. Although pigs from farms with different herd health and husbandry conditions the traditional view is that glucocorticoids are anti-­inflammatory, have different mean values.143 Therefore, the determination of Hp there is an increase in proinflammatory cytokines when there is a in the slaughterhouse can be of potential use for identifying herd cross-­activation of the immune system and glucocorticoids, espe- problems on farms.144 cially in conditions where stress precedes inflammation or in condi- Cranio-­ventral pulmonary consolidation (CVPC) and pleuritis are tions of chronic stress.151–­153 The multiple physiologic responses to the most common pathologic lesions found in the lungs of pigs at the stress are illustrated in Figure 3. The paradigmatic stress hormone, slaughterhouse, with M. hyopneumoniae and A. pleuropneumoniae cortisol, can be used as a stress marker but has large intraindividual being the most important primary respiratory pathogens, respec- variability, may be altered by other physiologic causes such as explo- tively.145 These diseases are associated with significant economic ration of the environment, exhibits a circadian rhythm, and is a poor losses. At the slaughterhouse, Hp concentrations were significantly marker for chronic stress.154 higher in animals with CVPC lesions compared with animals with- The specific effect of stress on APP concentrations is diffi- out these types of lesions.146 Significant differences in CRP and Hp cult to evaluate since, in many situations (eg, housing, transport), F I G U R E 3 Relationship between stress and the immune system. CRH: Corticotropin-­releasing hormone; ACTH: Adrenocorticotropic hormone. | 1939165x, 2023, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vcp.13220 by Readcube (Labtiva Inc.), Wiley Online Library on [09/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 58 SACO and BASSOLS there is concurrent psychologic stress, subclinical infections, and 5 | CO N C LU S I O N S traumatic lesions inherent in the crowding of animals. Besides the ethical aspects, the welfare of the animals during transport to The main limitation of using APPs is the lack of specificity. and lairage in the slaughterhouse is important since the impact of Nevertheless, this is also the main strength. Acute phase proteins stress is closely related to meat quality.155 The duration of trans- have been extensively investigated in diseases, but their use as mon- port affects Pig-­M AP and Hp responses; increased concentrations itoring tools for production and welfare purposes deserves to be are seen with longer transport times, and CRP and SAA concen- recognized and further explored. One important bottleneck identi- trations increase after shorter transport times, probably because fied long ago is the standardization and harmonization of diagnostic responding proteins.156–­159 Conditions accom- they are faster-­ testing and the establishment of reference intervals. panying transport (eg, access to water, food, or the presence of sawdust) and alterations in feeding patterns can also affect animal AC K N OW L E D G M E N T S welfare, cause stress, and induce higher concentrations of Pig-­ We thank Raquel Pato and Raquel Peña, for their years of work MAP, Hp, and CRP.157,160 Heat stress has also been reported to at the Servei de Bioquímica Clínica Veterinària at the Universitat 161 induce an acute phase response. Autònoma de Barcelona. In addition, we are grateful to veterinarians Stress in pigs has been widely studied in our laboratory. Pigs and animal science researchers for our multiple collaborations. that are housed in high-­density pens had higher Pig-­MAP concen- trations than those kept in larger spaces.162 Sows have commonly D I S C LO S U R E been housed under field conditions in individual stalls throughout The authors indicated no affiliations or financial involvement with pregnancy because it eases animal handling, reduce social stress, any organization or entity with a financial interest in, or in financial and allows appropriate feeding. Because this individual housing sys- competition with, the subject matter or materials discussed in this tem is considered stressful and harmful for animals, this practice has article. been banned by the European Union (CD 2001/88/EC). 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