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How to Interpret Serum Amyloid A Concentrations
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1. Introduction
The role of the clinical veterinarian encompasses many features of medical practice, but in many cases starts with a simple dichotomization: is this animal normal or abnormal? This can include the question, “is it lame or sound,” but often also includes, “is it sick or well?” A thorough history and physical examination will often reveal how to stratify the patient, but in cases of subtle disease especially for horses in high level competition, mild and early signs of infection and inflammation may be occult yet significant. A reliable test for infection or inflammation, therefore, can have an extremely valuable place in the clinician’s armamentarium. Good tests allow for some degree of quantification both to allow the practitioner to assess the severity of the process and also to follow and document its response to therapy and track its resolution over time. The earliest of these tools was rectal temperature, in which fever signified a secondary indicator of increased cytokines such as tumor necrosis factor (TNF)-α and interleukin (Il)-1.1 However, over the past century, blood analysis has allowed us to quantify multiple inflammatory markers including the acute phase proteins such as fibrinogen, haptoglobin, α1-acid glycoprotein, C-reactive protein (mainly in humans), serum amyloid A (SAA), and many others, as well as secondary indicators such as white blood cell count and serum iron levels.2 Of these, fibrinogen has probably been the most heavily relied on for horses. It can be easily and inexpensively measured, but may be confounded by in vitro preanalytical microclot formation. However, its concentration only slowly increases in the 24 hours after induction of inflammation and often does not peak until 48 hours. In addition, there is often only a small increase (often only a 1–2-fold difference) from baseline,3 and thus mild inflammation cannot reliably be distinguished from normal values. Nonetheless, any method that detects inflammation in the horse probably must outperform fibrinogen in one or more of these factors: accuracy, ease of interpretation, cost, and ease of use.
SAA is the major acute-phase protein of the horse (and most other mammals), and is produced pre-dominantly by the liver as a systemic manifestation of the body’s response to inflammation. It exists in equine plasma as one of three isoforms of apolipo-protein and is complexed to high-density lipoprotein in circulating blood.4 First investigated in hoeses in the 1980s,5,6 its clinical use as a marker of inflammation is probably eclipsed by fibrinogen as a function of assay availability rather than diagnostic inferiority. The advantages of SAA over fibrinogen include that it has both low/undetectable constitutive expression in normal animals but reaches levels of 100-1000-fold baseline values in clinical disease states.3 In addition, its rapid increase in concentration over 6–12 hours combined with a 30–120- minute half-life7 means that serum values track disease severity closely,3 and subsequent relapse or secondary infections result in similar response to primary infections.8 SAA is stable both at room temperature and refrigerated,9 can be measured using a relatively inexpensive stallside test9 or a variety of laboratory-based assays,10 can be performed using plasma as well as serum,11 and may be assessed using noninvasive samples such as saliva.12 Although there is some difference in precision and accuracy between assays, most available tests seem to be accurate enough within clinically relevant ranges to be acceptable to the practitioner.9,10,13
2. Materials and Methods
A review of the literature reveals many publications that evaluate the use of SAA as a tool for distinguishing healthy horses from those with local or systemic inflammation, and as a diagnostic and monitoring tool for specific conditions. To maximize utility of this compilation of clinical equine veterinary publications, they are presented by body system or disease process, and the review focuses on the most clinically relevant studies. The astute reader will notice that these references refer to SAA in mg/L, µg/mL, and ng/mL; the first two of these units are equivalent and the third represents one thousandth the concentration of the first. The authors’ original units are maintained throughout.
3. Results
SAA to Determine Infectious/Inflammation Versus Normal
Horses that are “not quite right” or performing poorly are often diagnostic challenges, and identifying mild inflammation and distinguishing it from noninflammatory differential diagnoses before its clinical signs declare themselves can stymie even the most meticulous clinician. A recent large study evaluated the SAA concentrations of hospitalized horses that had either local inflammation (gastric ulceration, abscesses, Streptococcus equi subsp equi infection), systemic inflammation (disease accompanied by fever, tachycardia, leukopenia/leukocytosis) or were otherwise healthy or had noninflammatory conditions.14 Patients with systemic inflammation had significantly higher SAA (mean, 1583 mg/L; range, 688 – 4000 mg/L) than horses with local or no inflammation, which had mean SAA concentrations of 343 mg/L (range, 37–1609 mg/L) and 5.6 mg/L (range, 1.8 –14.5 mg/L) respectively. This discrimination was more distinct than that of fibrinogen, in which the mean values of the three groups were 224, 181, and 128 mg/dL, respectively. Using receiver operator curve analysis, SAA had the highest accuracy for diagnosing inflammation (Fig. 1), but predictive modeling failed to generate useful algorithms.14 A similar study15 dichotomized horses into “clinically normal” and “clinically abnormal,” the latter of which included conditions as diverse as pneumonia, cholangiohepatitis, Streptococcus equi subsp equi infection, meningitis, enterocolitis, various forms of colic and neoplasia, and orthopedic infections. The clinically normal horses had a mean SAA of 6.8 mg/L (range, 0.1– 26.6 mg/L), whereas the clinically abnormal horses had a mean SAA of 71.7 mg/L with a range of 0.1–3,800. In the same cases, mean fibrinogen values (ranges) were 349 mg/dL (100 – 800 mg/dL) and 514 mg/dL (100 –1200 mg/dL), respectively. For discrimination of clinically normal horses from clinically abnormal horses, SAA had sensitivity of 53% and specificity of 94% (diagnostic accuracy, 75%), whereas using white blood cell count, and plasma fibrinogen concentration and mean albumin:globulin ratio, accuracy ranged from 59 to 62%. The authors also showed data from six cases comparing the resolution of inflammatory markers over time (Fig. 2) and concluded that “SAA concentration can provide valuable information regarding the clinical state of horses and may be more useful for patient monitoring and as a prognostic indicator than are traditional markers of inflammation.”15
Foals have been shown to have similar baseline values of SAA compared with adults, the kinetics of its rise and resolution seems grossly similar,16–19and SAA is higher in animals with bacterial infections than in those with nonbacterial or uncertain diagnoses.18 [...]
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