Summary

Acute phase proteins (APP) are remarkable biomarkers of inflammation related to infection, autoimmune disease, neoplasia, stress, and trauma. Considerable research and studies of clinical applications support the use of APP in bloodwork.

Introduction

The acute phase response (APR) is an integral part of the early innate immune response and a complex systematic inflammatory process that begins with a local stimulus such as a response to injury or infection and then the production of numerous cytokines which are produced in part by the first responding macrophages and monocytes.^1-3 Some of these cytokines signal the liver to initiate or upregulate the expression of an estimated 200 acute phase proteins (APP) each having a unique function.¹

The expression of APP can increase or decrease with an ongoing APR.^2-4 Major APP can increase 10- to 1,000-fold and are often present in negligible levels in normal animals. The increase is rapid and often occurs within 24 hours. In contrast, mild and moderate APP are present in detectable levels in normal animals with increases may be 2- to 10-fold for moderate APP and less than 2-fold for minor APP. Peak expression is delayed 4–6 days after insult and elevated levels will persist and slowly normalize after resolution of the inflammatory process. Albumin is classified as a negative APP as it decreases in ongoing APR.

An ongoing APR can be reflected in fraction changes in protein electrophoresis.¹ Newer automated and semi-automated methodologies including enzyme-linked immunosorbent assay, immunoturbidity, and colorimetry has been employed to quantitate specific APP. In the antibody-based protocols, methods and reagents must be individually validated for each species.⁵

Companion and Large Animals

Major APP including C-reactive protein (CRP) and serum amyloid A (SAA) have been well documented in cats, dogs, horses, and cows.^1-4 Increased expression has been clearly linked to primary issues like infection and trauma and it is recognized that APP provide different aspects of the APR than traditional measures like total WBC count, neutrophil count, and A/G ratio.^2-4 In addition, major APP provide key prognostic value, aid in monitoring surgery complications, inflammation and treatment thereof, and can help to decrease the period of antimicrobial use.

Birds

Studies in chickens have dominated the literature on APP expression in birds with document changes in SAA, PIT-54 (analog to HP), transferrin and alpha-1 acid glyoprotein.^6,7 SAA expression increases in falcons with aspergillosis.^8,9 As most commercial reagents are not cross reactive with avian APP, protein electrophoresis provides very good sensitivity for ongoing APR. It provides a broad impression of different globulin changes and is the only valid method (vs. chemistry analyzers) to quantitate albumin which is an important and sensitive negative APP in birds.¹⁰

Reptiles

Attempts to validate commercially available SAA antibodies in most reptiles have failed to date. Soft-shell turtles experimentally infected with gram negative bacteria showed 1,000-fold increased SAA expression (at the RNA level).¹¹ Haptoglobin (or hemoglobin binding activity) has been demonstrated in box turtles, loggerhead turtles, inland bearded dragons, and rattlesnakes among others.^12,13

Exotic Companion Mammals

Rats and mice have interesting differences in APP expression with the production of other APP and roles of major APP different from more mainstream mammalian species.⁴ There has been little to no description of APP expression in guinea pigs, hamsters, and gerbils.

CRP expression has been described in rabbits with suspected Encephalitozoon cuniculi infection.¹⁴

Elevated CRP levels acted as an adjunct diagnostic test to improve the specificity of serologic titers against this organism and served as a prognostic indicator. SAA has also been identified as a major APP in this species.¹⁵

Ferret SAA was found to be increased 2- to 5-fold in clinically abnormal ferrets.¹⁶

Other Species

APP expression has been well documented using RNA quantitation in several species of fish.¹⁷ Attempts to document APP expression in a trauma model in koi were not successful and may have been related to lack of reagent cross reactivity and experimental design.¹⁸ Reference intervals have been generated for the white-spotted bamboo shark and some commercial CRP reagents have been validated for use in the bonnethead shark.¹⁹ A wide range of published and ongoing studies have validated the use of APP in many wildlife species and in some species, these tests have been implemented as part of the standard of care for captive animals, for prognostic value in rehabilitation setting, and in population studies of free-ranging animals.^2,20

References

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<![if !supportLists]>20.  <![endif]>Bertelsen MF, Kjelgaard-Hansen M, Grondahl C, et al. Identification of acute phase proteins and assays applicable to nondomesticated mammals. J Zoo Wildl Med. 2009;40:199–203.