Acute-phase response (APR) refers to a complex systemic reaction occurring shortly after tissue injury. APR, as part of the innate host defense system, is a nonspecific response to various possible causes, including infectious, immunologic, neoplastic, or traumatic processes. APR is mainly mediated by proinflammatory cytokines, including interleukin-6, interleukin-1, and tumor necrosis factor-α secreted by local inflammatory cells such as monocytes and macrophages. This induces changes in plasma proteins, produced mainly in the liver, called acute-phase proteins (APPs). Major and minor positive APPs (eg, C-reactive protein [CRP], serum amyloid A, haptoglobin, alpha-1-acid glycoprotein, ceruloplasmin, fibrinogen) increase in the APR, and negative APPs (eg, albumin, transferrin) decrease. In dogs, CRP is a major APP. Its serum concentration is very low in healthy animals, but increases rapidly after stimuli, with a lag-phase of ~4 h, reaching peak concentrations ~24 h after the stimulus and then normalizing quickly during recovery. These characteristics make CRP a useful marker of ongoing inflammatory activity.
C-reactive protein increases in various infectious disease processes as well as in immune-mediated and neoplastic diseases in dogs.[5-13] CRP has been shown to be useful in differentiating disease processes such as pyometra from endometrial hyperplasia as well as steroid-responsive meningitis and arteritis from other neurologic diseases and in identifying early postoperative complications.[9, 14, 15]
Canine lower respiratory diseases and cardiac diseases are common clinical entities in small animal practice. Many of these diseases present with similar signs and a definite diagnosis often requires advanced methods, including bronchoscopic sampling and echocardiography. Because these methods are not always readily available and airway sampling requires anesthesia, a need exists for new noninvasive markers, especially for the detection of bacterial infections. Early precise diagnosis decreases unnecessary antimicrobial use and lowers the risk of development of antimicrobial resistance. Increases in CRP previously have been identified in studies describing a variety of infectious diseases, including dogs with pneumonia and laboratory dogs with experimentally induced bacterial bronchitis, as well as in dogs with chronic valvular disease and congestive heart failure.[16-20] These studies have applied different methods for CRP analysis, preventing comparison of CRP concentrations among diseases. Studies describing CRP concentrations in a cohort of dogs with clinically defined different lower airway diseases are lacking. In human respiratory medicine, CRP is widely studied and used especially for identifying community-acquired pneumonia (CAP) and for assessing the need for antimicrobial therapy.[21-23]
The purpose of this study was to investigate serum CRP concentrations in various canine respiratory diseases and to examine whether CRP can be used as a biomarker in the diagnosis of bacterial respiratory diseases.
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- Materials and Methods
Dogs with bacterial lower airway diseases had increased CRP concentrations compared with dogs that had noninfectious diseases. The highest CRP concentrations were noted in dogs with BP, which had significantly higher CRP concentrations than healthy dogs or dogs from the BTB, CB, EBP, CIPF, or CPE disease groups. Our findings are in accordance with earlier studies by Nakamura et al and Yamamoto et al who reported increased CRP concentrations in dogs with bronchopneumonia, severe pneumonia, or “wild pneumonia” (a term used and not further defined by authors of the original article).[16, 17]
We noted that BP was identified with 100% specificity when CRP was >100 mg/L and ruled out with 100% specificity when CRP was <20 mg/L when signs had lasted >24 h. This finding is important because CRP concentration increases within 24 h after an inciting stimulus, and in the very early phase of BP development CRP production may not have developed to the full extent. According to the findings in this study, CRP concentrations between 20 and 100 mg/L may be found in dogs with several different respiratory diseases, and therefore are limited in their diagnostic value. In human medicine, CRP is widely used as an important biomarker in the diagnosis of CAP, and current guidelines recommend measuring CRP in patients suspected with CAP.[37, 38] According to these guidelines, CAP is considered very likely when CRP is >100 mg/L in a patient with compatible clinical presentation and unlikely when CRP is <20 mg/L and clinical signs have lasted >24 h. Similar to BP, CPE often presents with acute dyspnea or tachypnea. Thus, distinguishing between these conditions is sometimes difficult, especially before or in the absence of thoracic radiographs or echocardiography. Therefore, our results indicate that CRP has potential for use in dogs, similar to that in human medicine, contributing markedly to the diagnosis of BP.
In dogs with BTB, CRP was significantly higher than in dogs with other lower airway diseases presenting with cough (CB, EBP) or in healthy controls. Increases in CRP were mild (35–49 mg/L), and although significantly higher, there was marked overlap among groups. These findings indicate that increased CRP in a dog presenting with cough may arouse suspicion of bacterial bronchitis, but normal CRP does not rule out bacterial bronchitis. Yamamoto et al studied induced B. bronchiseptica bronchitis in laboratory dogs and found marked increases in CRP in the first 5 days after inoculation. CRP concentration returned nearly to normal within 10 days of inoculation. It would be interesting to compare these findings with those of naturally occurring BTB.
Unexpectedly, prior antimicrobial use did not affect CRP concentration in dogs with either BTB or BP; a similar finding has been reported in humans. This finding may be attributable to inadequate tissue penetration, inappropriate antimicrobial dosage, recent initiation of therapy, or bacterial resistance. The majority of patients with BP had received previous antimicrobial treatment, and bacteria were found in only 59% of respiratory samples in primary culture. This observation is in accordance with findings in human medicine, where identification of the causative bacterial organism is challenging, and negative results (up to 60% of samples) are common.[38, 39] Therefore, respiratory tract sampling is not a part of the routine diagnostic evaluation in humans with suspected CAP.[37-39] We believe that 3 of the dogs in the BP group that had neutrophilia in BALF or TTW samples, but a negative culture result represented such cases because they showed a rapid response and complete clinical and radiographic recovery with antibiotic treatment. Based on these findings, it may be reasonable to follow similar recommendations in veterinary medicine concerning diagnosis of uncomplicated cases of pneumonia in dogs.
The highest CRP concentrations in dogs with noninfectious lower respiratory tract diseases were observed in dogs with severe dyspnea leading to death or euthanasia (1 dog with CIPF [CRP 75 mg/L] and acute respiratory distress syndrome and 1 dog with CPE [CRP 86 mg/L]). However, in most dogs with CIPF and CPE, CRP concentrations were low (mean 16.8 mg/L; range, 5–32 mg/L). Cunningham et al described mild-to-moderate increases in CRP in dogs with congestive heart failure, which is in accordance with findings in our study. In people, CRP has been shown to increase with increasing severity of congestive heart failure.[40, 41]
To further understand the interrelationships of CRP, correlations with other clinical parameters were evaluated. In all groups combined, CRP was positively correlated with other markers of inflammation, including body temperature, blood leukocyte count, blood segmented and band neutrophil counts, and BALF neutrophil percentage. This finding was not unexpected because the same pro-inflammatory cytokines responsible for stimulating APR are also important mediators of fever and neutrophil production in bone marrow.[42, 43] However, these correlations were not found in the BP group. This can be partially explained by different timing of physiologic events in relation to CRP measurement in acute BP such as a delay in neutrophil production in early BP and a rapid decrease in body temperature after initiation of antimicrobial therapy. Interestingly, duration of signs did not correlate negatively with CRP in dogs with BTB, CPE, or BP. This finding is in contrast to previously published results and warrants further research before drawing any conclusions.
This study was intentionally designed to exclude dogs with other concurrent conditions capable of increasing CRP concentrations. For this reason, we cannot assess the applicability of CRP measurements in patients with respiratory disease and several other concurrent infectious, inflammatory, or neoplastic conditions. Certain neoplastic diseases have been demonstrated to result in significant increases in CRP potentially linked to tissue inflammation and necrosis induced by the tumor. However, it remains to be investigated whether patients with pulmonary neoplasia or pleural diseases can be differentiated from patients with BP using CRP measurement. Other potential implications of CRP in canine respiratory medicine include the role of CRP as an indicator of treatment response and as a possible prognostic marker in patients with severe pneumonia.
In conclusion, CRP is significantly increased in dogs with BP relative to healthy dogs and dogs with BTB, CB, EBP, CIPF, or CPE, enabling its use as an additional diagnostic biomarker in BP. Moreover, increases in CRP are not typical in patients with CB, EBP, or CIPF, and if encountered in such patients, presence of a secondary infectious process should be suspected.