C-Reactive Protein in Dogs: A Review for the General Practitioner

Positive acute-phase proteins are produced by the liver in response to tissue damage and play a key role in innate responses to injury and infection. Members of this group include C-reactive protein (CRP), haptoglobin, and serum amyloid A. Of these, CRP is the most well-established. It was first identified in the 1930s in humans with pneumococcal pneumonia and is now widely regarded as a sensitive biomarker of inflammation in human patients with a range of disorders. Despite this long-standing history in human medicine, measurement of CRP has only recently gained traction in the veterinary community.

In healthy dogs, CRP concentrations are generally less than 20 mg/L (i.e., 20 µg/mL). However, hepatic synthesis of CRP is rapidly stimulated by interleukins 1 and 6, resulting in increased serum levels within 4 to 24 hours of infection or the onset of inflammation. Depending on the nature of the insult or injury, concentrations may increase by 10- to 1000-fold, with a peak response between 24 and 48 hours. CRP levels typically begin to decline 18 to 24 hours after the initiation of appropriate treatment or mitigation of the inciting cause.¹

In dogs, increases in CRP have been reported in patients with a range of conditions, including numerous infections (e.g., parvoviral enteritis, pyometra), sterile inflammatory conditions (e.g., pancreatitis), and cancers (e.g., lymphoma).² As serum concentrations are not influenced by age, sex, or breed, this biomarker offers significant promise as an aid to the diagnosis of a wide range of diseases.

When Is it Helpful to Measure CRP?

In patients presenting with signs of inflammation such as pyrexia, depression, or dehydration, practitioners have traditionally relied on hematologic findings, along with serum globulin concentrations, to assess disease severity. Decreases in negative acute-phase proteins such as albumin may also be informative. However, CRP appears to be a more sensitive laboratory marker for identification and monitoring of inflammation in dogs.³ White blood cell counts, for example, may remain elevated for several days despite resolution of the underlying inflammatory condition. In addition, treatment protocols that rely on glucocorticoids may induce a persistent leukocytosis, despite effective management of the underlying disease.

Because CRP increases between 4 and 24 hours after the initiation of systemic inflammation, elevated concentrations are expected when the patient is first presented. Subsequent measurements should be performed within 18 to 24 hours of the initiation of treatment to assess response. Follow-up CRP concentrations can be measured as necessary to monitor the ongoing response to therapy.

What Do We Know About CRP in Dogs?

CRP concentrations have been used to identify inflammation in numerous conditions, many of which are listed in BOX 1.^4-17 More data are available on the usefulness of CRP in dogs with specific conditions; this information is summarized below.

Pneumonia

Coughing and tachypnea are common presenting complaints for canine patients in both general and emergency practices. Although radiographic findings may narrow down the list of possible causes, it can be difficult to establish a definitive diagnosis and determine the need for antibiotic therapy without invasive testing (see Case Example sidebar).

Case Example: C-Reactive Protein (CRP) Concentrations in a Dog With Pneumonia

A 6-year-old male castrated miniature dachshund presented with acute-onset cough and lethargy. The dog had a long-standing history of aspiration pneumonia secondary to idiopathic megaesophagus. Thoracic radiographs (FIGURE 1) were consistent with aspiration pneumonia. The patient’s CRP level was greater than 60 mg/L (reference range, <10 mg/L) and he was started on oral amoxicillin/clavulanate.

FIGURE 1A. Left lateral thoracic radiographic image taken at presentation. (A AND B) There is a marked alveolar pulmonary pattern within the right cranial and right middle lung lobes (circled). (A) An air-filled esophagus is evident (arrowheads). Courtesy of Texas A&M University Diagnostic Imaging Service

FIGURE 1B. Ventrodorsal thoracic radiographic image taken at presentation. (A AND B) There is a marked alveolar pulmonary pattern within the right cranial and right middle lung lobes (circled). Courtesy of Texas A&M University Diagnostic Imaging Service

Follow-up radiographs taken 3 weeks later (FIGURE 2) showed substantial improvement; the patient was reported to be active and eating well. However, there was a persistent unstructured interstitial pulmonary pattern in the right cranial lung lobe. This was likely fibrosis secondary to prior pneumonia, but ongoing active disease could not be excluded based on radiographic findings alone. CRP was 10 mg/L at this time; antibiotics were therefore discontinued.

FIGURE 2A. Left lateral thoracic radiographic image taken after 3 weeks of antibiotic therapy. The previously described alveolar pattern throughout the right cranial and right middle lung lobes is resolved. (A) There is a minimal unstructured interstitial pattern in the region of the right cranial lung lobe in the left lateral view (blue arrowheads). The entire intrathoracic esophagus remains moderately dilated with gas (white arrowheads). Courtesy of Texas A&M University Diagnostic Imaging Service

FIGURE 2B. Ventrodorsal thoracic radiographic image taken after 3 weeks of antibiotic therapy. The previously described alveolar pattern throughout the right cranial and right middle lung lobes is resolved. Courtesy of Texas A&M University Diagnostic Imaging Service

In a prospective study of 106 dogs with various respiratory diseases and 72 healthy controls, median CRP concentrations were significantly higher in dogs with bacterial pneumonia (121 mg/L) than in those with eosinophilic bronchopneumopathy (5 mg/L), chronic bronchitis (13 mg/L), pulmonary fibrosis (17 mg/L), or cardiogenic pulmonary edema (19 mg/L).¹⁸ In another study of dogs with pulmonary parenchymal disease, CRP concentrations greater than 100 mg/L were 100% specific for bacterial pneumonia (reference interval, <10 mg/L); concentrations less than 20 mg/L reliably excluded this possibility.⁴ However, there was no correlation between CRP concentration and disease severity in this patient population.⁴

In addition to guiding decisions regarding the need for antibiotic therapy, measurements of CRP may be used to determine the duration of treatment in dogs with bacterial pneumonia. Concentrations normalize with cessation of active disease, and serial measurement of CRP may be used to confirm resolution of infection. This approach appears superior to simply extending treatment for 2 weeks beyond the resolution or stabilization of radiographic abnormalities.^4,19

Acute Pancreatitis

Studies in human patients with acute pancreatitis indicate that CRP concentrations correlate with disease severity and provide useful prognostic information.^20-22 In humans, severely elevated levels of CRP (>150 mg/L) have been used to help diagnose necrotizing pancreatitis.²¹ Therefore, the utility of CRP in dogs with acute pancreatitis has been of interest in veterinary medicine.

In a retrospective study of 22 dogs with acute pancreatitis treated at a veterinary teaching hospital, CRP measurements for the nonsurvivors (n = 7) were significantly higher than for the survivors (n = 15) on days 3 (68 mg/L versus 25.5 mg/L) and 4 (66 mg/L versus 16 mg/L) of hospitalization (reference interval, <7 mg/L). Persistently elevated CRP levels were also associated with a poorer prognosis in this population.¹¹

A prospective study evaluated 2 clinical severity scores, CRP concentrations, and pancreatic lipase immunoreactivity in 13 dogs with acute pancreatitis. Interestingly, measurements of pancreatic lipase immunoreactivity were better correlated with clinical severity scores than CRP concentrations when all parameters were assessed on a daily basis.²³ However, 10 of the 13 dogs in this study had concurrent diseases that may have affected CRP measurements. Larger studies are clearly needed to determine the clinical application of CRP in dogs with pancreatitis.

Immune-Mediated Diseases

Measurements of CRP have been reported in dogs with immune-mediated hemolytic anemia. As expected, concentrations were increased 25-fold at the time of diagnosis and decreased with appropriate treatment. Normalization (reference range, <8.9 mg/L) occurred in 7 of 10 surviving dogs within 2 weeks.²⁴ However, there was no correlation between the magnitude of increase in CRP levels at the time of diagnosis and patient survival (nonsurvivors, 194 mg/L; survivors, 242 mg/L).²⁴

Similarly, CRP concentrations are higher in dogs with immune-mediated polyarthropathy (IMPA). In a prospective study of 9 dogs with IMPA, CRP levels at the time of diagnosis ranged from 76.7 to 195 mg/L; this was markedly higher than for the 6 healthy controls (mean, <6.3 mg/L). CRP concentrations declined after initiation of immunosuppressive treatment and were significantly lower than baseline after 2 weeks.⁶ Importantly, CRP levels were correlated with synovial inflammation; an increase in CRP during or after treatment is therefore an indicator of relapse.⁶

Postoperative Infection

Surgical procedures are associated with increased CRP concentrations in dogs. In 1 study, values increased 16- to 45-fold within 24 to 48 hours and were particularly elevated in patients undergoing orthopedic procedures associated with significant surgical trauma.²⁵ However, CRP concentrations routinely normalized by the time of suture removal despite persistent elevations in white blood cell counts.^25,26 These findings suggest that CRP is a more reliable indicator of postsurgical inflammation in patients undergoing orthopedic surgery than routine hematologic parameters.

In bitches undergoing ovariohysterectomy for pyometra, CRP concentrations measured 4 days postoperatively were found to be higher in those with incision site infections. Affected dogs had a mean CRP concentration of 296.6 mg/L, compared with approximately 100 mg/L for the uninfected cohort.¹² Measurement of CRP levels in the postoperative period may therefore provide early evidence of complications such as infection.

Neoplasia

Elevations in CRP concentrations have been reported in dogs with mammary tumors, lymphoma, mast cell tumors, sarcomas, and various metastatic neoplasias.^8,9,26,27 In 60 dogs with mammary tumors, 77% of those with metastases had a CRP concentration above the upper end of the reference range.⁹ Elevations in CRP were also reported in dogs with benign and solitary tumors; an increased value is therefore not conclusive evidence of metastatic disease.⁹ The highest CRP levels seen in this study were found in dogs with ulcerated primary tumors (median, 114.4 mg/L).⁹ In a recent study evaluating dogs (N = 147) with CRP concentrations greater than 100 mg/L, 17 (12%) were found to have malignant neoplasia.²⁸

In a prospective study of dogs with mast cell tumor or sarcoma, CRP levels were significantly higher (104.1 mg/L and 262.1 mg/L, respectively) in affected dogs than in healthy controls (19.7 mg/L).⁸ Tumor grade did not have a significant effect on CRP concentrations.⁸

Discospondylitis

In humans with vertebral osteomyelitis, increased CRP concentrations are associated with shorter periods of preceding symptoms and higher mortality rates.^29,30 In a retrospective study of dogs diagnosed with bacterial discospondylitis via magnetic resonance imaging, 11/18 (61.1%) had an elevated CRP concentration; this was >5 times the upper limit of the reference range in 10 dogs.¹⁶ In addition, this biomarker was more sensitive for the presence of infection than both fever and leukocytosis. Similar results were described in another study in which 14/16 dogs with imaging findings indicating discospondylitis had an elevated CRP concentration at the time of diagnosis (median, 100.7 mg/L).³¹ Back pain was present in all dogs; 12 were febrile but just 6/16 had a leukocytosis.³¹

Importantly, serum CRP concentrations should be within the reference range in dogs with intervertebral disc extrusion; an elevated CRP concentration in a dog with spinal pain is therefore strongly suggestive of an inflammatory or infectious spinal condition.²⁷ Practitioners should bear in mind, however, that elevated CRP concentrations are also seen in patients with steroid-responsive meningitis–arteritis and is therefore not specific for discospondylitis.³²

How Can We Measure CRP?

Several in-house systems offer CRP measurement for dogs; both the Catalyst CRP Test (IDEXX, idexx.com) and the Canine CRP Immunoassay (Gentian, gentian.com) have been validated for use with canine serum.³³ Alternatively, samples may be submitted to major veterinary reference laboratories (e.g., Antech, Idexx), the University of Cornell Clinical Pathology Laboratory, or the Texas A&M Gastrointestinal Laboratory. Practitioners should contact the laboratory directly to verify preferred sample type and shipping requirements. This analyte is stable at 22 °C (72 °F) to 4 °C (39 °F) for 14 days³³; therefore, special handling or shipment on ice is not usually necessary.

Results may be influenced by the specific methodology used, and reference intervals may vary between systems and laboratories. Consequently, data from different devices cannot be compared directly or used interchangeably. The same methodology should be used when assessing an individual’s response to therapy or when looking for trends.

Summary

Biomarkers such as CRP are likely to play an increasing role in the care of companion animals, as they provide information that may not be available with routine laboratory testing. More studies are needed to better define the role of CRP as both a prognostic indicator and a noninvasive tool for the management of dogs with a range of inflammatory diseases, but the available data suggest substantial promise. Practitioners are encouraged to become familiar with the indications for measurement of CRP levels in dogs and to consider incorporating CRP measurements into patient care protocols.