Acute phase proteins (APPs) have been used as biomarkers of inflammation, infection and trauma for decades in human medicine but have been relatively under-utilised in the context of veterinary medicine. However, significant progress has been made in the detection, measurement and application of APPs as biomarkers in both companion and farm animal medicine over recent years. In the dog, C-reactive protein, haptoglobin and serum amyloid A have been identified as significant diagnostic 'markers' of steroid-responsive meningitis-arteritis, while in cats and cattle haptoglobin and alpha(1) acid glycoprotein and haptoglobin and serum amyloid A have proved valuable biomarkers of disease, respectively. In dairy cattle, haptoglobin and a mammary-associated serum amyloid A3 isoform, produced by the inflamed mammary gland during episodes of mastitis, have great potential as biomarkers of this economically important disease. Understanding the use of APP as biomarkers of inflammatory conditions of domestic animals has expanded significantly over recent years, and, with the insights provided by ongoing research, it is likely that these compounds will be increasingly used in the future in the diagnosis and prognosis of both companion and farm animal disease.

Acute phase proteins: Biomarkers of infection and inflammation in veterinary medicine

Tumors of the mammary gland

Acute phase proteins (APP) were first identified in the early 1900s as early reactants to infectious disease. They are now understood to be an integral part of the acute phase response (APR) which is the cornerstone of innate immunity. APP have been shown to be valuable biomarkers as increases can occur with inflammation, infection, neoplasia, stress, and trauma. All animals--from fish to mammals--have demonstrable APP, but the type of major APP differs by species. While the primary application of these proteins in a clinical setting is prognostication, studies in animals have demonstrated relevance to diagnosis and detection and monitoring for subclinical disease. APP have been well documented in laboratory, companion, and large animals. With the advent of standardized and automated assays, these biomarkers are available for use in all fields of veterinary medicine as well as basic and clinical research.

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Acute phase proteins in animals.

Sepsis, the systemic inflammatory response to infection, represents the major cause of death in critically ill veterinary patients. Whereas important advances in our understanding of the pathophysiology of this syndrome have been made, much remains to be elucidated. There is general agreement on the key interaction between pathogen-associated molecular patterns and cells of the innate immune system, and the amplification of the host response generated by pro-inflammatory cytokines. More recently, the concept of immunoparalysis in sepsis has also been advanced, together with an increasing recognition of the interplay between regulatory T cells and the innate immune response. However, the heterogeneous nature of this syndrome and the difficulty of modeling it in vitro or in vivo has both frustrated the advancement of new therapies and emphasized the continuing importance of patient-based clinical research in this area of human and veterinary medicine.

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The Immunopathology of Sepsis: Pathogen Recognition, Systemic Inflammation, the Compensatory Anti‐Inflammatory Response, and Regulatory T Cells

Salivary cortisol concentrations and behavior in a population of healthy dogs hospitalized for elective procedures

Background: In veterinary medicine, there is increasing interest in measuring acute phase proteins as a tool in the diagnosis and monitoring of neoplastic diseases. Although mammary neoplasms are the most common type of cancer in dogs, acute phase proteins have not been extensively evaluated in dogs with mammary tumors.

Objectives: The aim of this study was to evaluate serum haptoglobin (Hp) and C-reactive protein (CRP) concentrations in the dogs with mammary tumors and assess their potential association with malignancy.

Methods: A retrospective study of dogs with mammary tumors was performed. Serum concentrations of CRP and Hp were determined in healthy control dogs (n=20) and dogs with mammary tumors before surgery (n=41). Mammary tumors were grouped as carcinomas (n=24), fibrosarcoma (n=1), malignant mixed tumors (n=7), benign mixed tumors (n=6), and adenomas (n=3). CRP and Hp concentrations were compared in dogs with different tumor types and were also compared based on tumor size, lymph node infiltration, skin ulceration, fixation to underlying tissue, and time between tumor identification and removal.

Results: Hp concentration was significantly (P<.043) higher in dogs with mammary tumors (median 2.03 g/L, range 0.09–2.94 g/L) compared with controls (1.38 g/L, range 0.08–3.00 g/L), but the range of values overlapped considerably. CRP concentration was higher in dogs with carcinomas (4.70 mg/L, range 0.63–128.96 mg/L) vs controls (2.11 mg/L, range 0.25–6.57 mg/L) (P=.0008) and in dogs with ulcerated skin (14.8 mg/L, range 5.7–128.9 mg/L, n=3) compared with those without ulceration (2.4 mg/L, range 0.11–30.3 mg/L, n=38) (P=.048).

Conclusions: Serum Hp and CRP do not appear to have value in diagnosing or predicting malignancy of mammary tumors in dogs. Higher CRP concentrations in dogs with mammary carcinoma suggest a role for inflammation in this tumor type.

Evaluation of serum haptoglobin and C‐reactive protein in dogs with mammary tumors

Objective—To study the effects of a synthetic, dog-appeasing pheromone (sDAP) on the behavioral, neuroendocrine, immune, and acute-phase perioperative stress responses in dogs undergoing elective orchiectomy or ovariohysterectomy. Design—Randomized, controlled clinical trial. Animals—46 dogs housed in animal shelters and undergoing elective orchiectomy or ovariohysterectomy. Procedures—Intensive care unit cages were sprayed with sDAP solution or sham treated with the carrier used in the solution 20 minutes prior to use. Dogs (n = 24 and 22 in the sDAP and sham treatment exposure groups, respectively) were placed in treated cages for 30 minutes before and after surgery. Indicators of stress (ie, alterations in behavioral, neuroendocrine, immune, and acute-phase responses) were evaluated perioperatively. Behavioral response variables, salivary cortisol concentration, WBC count, and serum concentrations of glucose, prolactin, haptoglobin, and C-reactive protein were analyzed. Results—Behavioral response vari...

Effect of a synthetic appeasing pheromone on behavioral, neuroendocrine, immune, and acute-phase perioperative stress responses in dogs

The aim of this trial was to describe the behavioural, neuroendocrine, immune and acute phase stress responses in dogs undergoing elective surgery in normal, clinical practice conditions. Sixteen dogs were submitted to elective orchiectomy or ovariohysterectomy using a standardised surgical protocol. Each animal was confined to the Intensive Care Unit during pre- and post-surgery and perioperative behavioural, neuroendocrine, immune and acute phase responses were studied. Behavioural categories, cortisol, prolactin, white blood cell, C-reactive protein and haptoglobin variation were evaluated. Values at different times were compared with basal values shown by the dog in its usual environment. Communicative and explorative behaviours showed high occurrence pre-surgery and were inhibited post-surgery. Decreases in post-surgery activity, interactive behaviours and changes in waking/sleeping patterns were observed. The most sensitive marker of psychological stress, cortisol, in comparison with basal values, showed a significant increase both during pre- and post-surgery confinement in the ICU cage. Prolactin values were characterized by a significant decrease early into the post-surgery period. The immune response was characterized by long-term neutrophilia and monocytosis, but by short-term lymphopaenia and eosinopaenia, limited to the early post-operative period. With regard to the acute phase response, both C-reactive protein and haptoglobin showed a long-term increase, post-surgery. Changes in behavioural, haematological and biochemical markers showed that perioperative stress represents a major challenge to dog welfare.

Carlo Siracusa

Papers

Evaluation of serum haptoglobin and C‐reactive protein in dogs with mammary tumors

Effect of a synthetic appeasing pheromone on behavioral, neuroendocrine, immune, and acute-phase perioperative stress responses in dogs

Perioperative stress response in dogs undergoing elective surgery: variations in behavioural, neuroendocrine, immune and acute phase responses

25: Perioperative stress in dogs: Neuroendocrine and immune responses (Perioperative stress response in sheltered dogs)