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Contents

  1. Top of page
  2. Contents
  3. Introduction
  4. Risk Factors
  5. Aetiology and Pathogenesis
  6. Case History, Clinical Signs, Diagnosis and Treatment
  7. Laboratory Findings
  8. Differentiation of Pyometra and Mucometra
  9. The Local Uterine Inflammatory Response
  10. Future Management Strategies for Pyometra
  11. References

Pyometra is a common disease of female dogs. In Sweden, where approximately 90% of the dog population is intact (not neutered), nearly 25% of all female dogs are diagnosed with the disease before 10 years of age. In certain high-risk breeds, this risk of developing pyometra exceeds 50%. Various clinical signs associated with the genital tract as well as with systemic disease are present in dogs with pyometra. A frequent and serious consequence of the uterine infection is endotoxaemia and progression into the systemic inflammatory response syndrome (SIRS), or sepsis, and the disease is then regarded as a medical emergency. Acute phase proteins and inflammatory markers associated with SIRS and with the outcome as measured by length of hospitalization have been identified in blood samples. Recently, the inflammatory response in infected uterine tissue during pyometra has been more closely explored. The expression of many genes associated with chemokines, cytokines, inflammatory cell extravasation, anti-bacterial action, the complement system and innate immune responses and also a large panel of proteases are upregulated in the uterine tissue in pyometra. Products of certain upregulated genes may be detected systemically and used for diagnostic or prognostic purposes provided that tests are developed in the future. More knowledge of the complex local and systemic inflammatory response in pyometra may allow identification of novel disease biomarkers or future targets for treatment. In this article, clinical as well as molecular characteristics of the disease are reviewed.


Introduction

  1. Top of page
  2. Contents
  3. Introduction
  4. Risk Factors
  5. Aetiology and Pathogenesis
  6. Case History, Clinical Signs, Diagnosis and Treatment
  7. Laboratory Findings
  8. Differentiation of Pyometra and Mucometra
  9. The Local Uterine Inflammatory Response
  10. Future Management Strategies for Pyometra
  11. References

In countries where neutering of healthy dogs is not generally practiced, pyometra is one of the most common diseases affecting over 50% of all female dogs of some breeds before 10 years of age (Egenvall et al. 2001). The disease is characterized by uterine bacterial infection and inflammation with pus accumulating in the uterus in combination with systemic illness that is life-threatening in severe cases (Fransson 2003). Pyometra mainly affects middle-aged and older individuals but has been reported in ages ranging from 4 months to 18 years with a mean age for diagnosis of 6–8 years (Niskanen and Thrusfield 1998; Egenvall et al. 2001). The disease is more common and occurs at an earlier age in certain dog breeds, indicating that a genetic predisposition for pyometra exists (Niskanen and Thrusfield 1998; Egenvall et al. 2001).

Risk Factors

  1. Top of page
  2. Contents
  3. Introduction
  4. Risk Factors
  5. Aetiology and Pathogenesis
  6. Case History, Clinical Signs, Diagnosis and Treatment
  7. Laboratory Findings
  8. Differentiation of Pyometra and Mucometra
  9. The Local Uterine Inflammatory Response
  10. Future Management Strategies for Pyometra
  11. References

Increased risk of developing pyometra has been associated with hormone administration (oestrogen and progestagen compounds), whereas pregnancy has a somewhat protective effect (Niskanen and Thrusfield 1998). Importantly, pregnancy is not completely protective because the disease occurs in parous (even multiparous) individuals. In one recent breed- and age-matched case–control study, previous pregnancy was shown to be protective in some breeds, but not all (Hagman et al. 2011). Risk and protective factors may thus vary between different breeds. Uterine pathology such as cystic endometrial hyperplasia (CEH) and mucometra are believed to predispose the uterus for infection and subsequent pyometra.

Aetiology and Pathogenesis

  1. Top of page
  2. Contents
  3. Introduction
  4. Risk Factors
  5. Aetiology and Pathogenesis
  6. Case History, Clinical Signs, Diagnosis and Treatment
  7. Laboratory Findings
  8. Differentiation of Pyometra and Mucometra
  9. The Local Uterine Inflammatory Response
  10. Future Management Strategies for Pyometra
  11. References

In pyometra, bacteria ascending from the normal flora of the vaginal vault establish an infection of a progesterone-primed uterus. The predominant pathogen (in approximately 70% of the cases) is Escherichia coli, and the aetiological strains are associated with certain virulence factors including the ability to adhere to specific receptors in the endometrium (Krekeler et al. 2012). A serious consequence of the uterine infection is endotoxaemia and progression into the systemic inflammatory response syndrome (SIRS; Hagman et al. 2006). Systemic inflammatory response syndrome can be present either without infection or with infection (defined as sepsis) such as in pyometra, the presence of SIRS has previously been detected in over 50% of bitches suffering from the disease and has been linked with poorer prognosis and longer hospitalization (Fransson 2003; Hagman et al. 2006). High blood concentrations of endotoxin have been related to poor outcome (death) in dogs with pyometra and a rapid, reliable and cost-effective method for analysis would be clinically useful also in dogs. Analysis of a more stable indicator for endotoxin release, such as prostaglandin F-metabolite (PGM), could also prove valuable for such purposes (Hagman et al. 2006). In pyometra cases that are diagnosed with SIRS, the blood levels of C-reactive protein (CRP) and PGM are increased, and the levels associated with outcome as measured by hospitalization (Fransson 2003; Hagman et al. 2006). The inflammatory response induced subsides after surgical treatment of pyometra and concentrations of CRP, serum amyloid A (SAA) and haptoglobin can be monitored post-operatively and be useful for detecting complications and ongoing inflammation (Dabrowski et al. 2009). Disseminated bacterial infection or thromboemboli may spread the infection to different organs, for instance the brain, myocardium or uvea, and cause severe malfunctions.

Case History, Clinical Signs, Diagnosis and Treatment

  1. Top of page
  2. Contents
  3. Introduction
  4. Risk Factors
  5. Aetiology and Pathogenesis
  6. Case History, Clinical Signs, Diagnosis and Treatment
  7. Laboratory Findings
  8. Differentiation of Pyometra and Mucometra
  9. The Local Uterine Inflammatory Response
  10. Future Management Strategies for Pyometra
  11. References

A dog with pyometra is generally presented in diestrus, with a history of various signs associated with genital and systemic disease. A purulent vaginal discharge is often present (provided the cervix is open) and dehydration, polydipsia, polyuria, lethargy, abdominal pain, anorexia, vomiting and diarrhoea, fever or hypothermia, abnormal colour of the mucous membranes and elevated heart and respiratory rates may be observed (Fransson 2003). Recognition and diagnosis is straightforward in classic cases, but may be challenging in cases without vaginal discharge (closed cervix) and when the history and clinical picture are obscure. A preliminary diagnosis based on case history, physical examination, haematological and biochemical blood analyses, ultrasonography and/or radiography and bacteriological culturing or cytology of the vaginal/uterine discharge can be verified by histopathological examination of the uterine tissue. Pyometra is regarded as a medical emergency because rapid therapeutic intervention is necessary to prevent a fatal outcome. The safest treatment of pyometra is surgical ovariohysterectomy (immediate removal of the source of infection), which also prevents recurrence. The surgery is normally performed a soon as the general condition of the dog is stable. Medical treatment is an option in some selected cases to preserve fertility.

Laboratory Findings

  1. Top of page
  2. Contents
  3. Introduction
  4. Risk Factors
  5. Aetiology and Pathogenesis
  6. Case History, Clinical Signs, Diagnosis and Treatment
  7. Laboratory Findings
  8. Differentiation of Pyometra and Mucometra
  9. The Local Uterine Inflammatory Response
  10. Future Management Strategies for Pyometra
  11. References

In the haematological and blood biochemical examinations, there are many alterations that can be induced by pyometra (Fransson 2003; Hagman et al. 2006; Maddens et al. 2011). Leucocytosis, with neutrophilia and left shift in the differential white blood cell count, is often observed. Occasionally, leucopoenia is present, and this has been associated with poorer prognosis. A normocytic, normochromic anaemia is thought to reflect the chronicity of the disease, decreased erythropoesis because of toxic effects on the bone marrow, lack of available iron and loss of erythrocytes to the uterus. Dehydration often complicates the evaluation of anaemia. Thrombocytopenia may be a result of bone marrow toxic affection. Hypoalbuminaemia and hyperproteinaemia are frequent findings, reflecting loss of albumine via the kidneys and increased production of gammaglobulins. Renal malfunction is commonly observed in pyometra and elevated concentrations of alkaline phosphatase, bilirubin and cholesterol concentrations probably reflect intrahepatic cholestasis (Fransson 2003; Maddens et al. 2011). Alterations in acid-base balance and electrolyte levels are also not uncommon in dogs with pyometra.

Differentiation of Pyometra and Mucometra

  1. Top of page
  2. Contents
  3. Introduction
  4. Risk Factors
  5. Aetiology and Pathogenesis
  6. Case History, Clinical Signs, Diagnosis and Treatment
  7. Laboratory Findings
  8. Differentiation of Pyometra and Mucometra
  9. The Local Uterine Inflammatory Response
  10. Future Management Strategies for Pyometra
  11. References

It may sometimes be difficult to differentiate cases with potentially life-threatening pyometra from those with CEH/mucometra when a fluid-filled uterus is identified. The inflammatory response is, however, more pronounced in pyometra compared with CEH/mucometra as reflected by several laboratory parameters and increased levels of CRP and PGM (Fransson 2003; Hagman et al. 2006). Additionally, in bitches with pyometra, the general condition is more depressed, and clinical signs such as lethargy and gastro-intestinal disturbances are more common (Fransson 2003; Hagman et al. 2006).

The Local Uterine Inflammatory Response

  1. Top of page
  2. Contents
  3. Introduction
  4. Risk Factors
  5. Aetiology and Pathogenesis
  6. Case History, Clinical Signs, Diagnosis and Treatment
  7. Laboratory Findings
  8. Differentiation of Pyometra and Mucometra
  9. The Local Uterine Inflammatory Response
  10. Future Management Strategies for Pyometra
  11. References

In pyometra, the bacterial infection and endotoxins are potent inducers of an inflammatory response, which is apparent in the uterine tissue. Recently, the inflammatory response in the infected uterine tissue during pyometra has been more closely explored. In one study of the molecular patterns involved in the uterus in pyometra, numerous (>800) genes were found upregulated (Hagman et al. 2009). Many of these genes are associated with chemokines, cytokines, inflammatory cell extravasation, anti-bacterial action, the complement system and innate immune responses (Table 1). A major feature in pyometra uteri was the upregulated expression of a large panel of proteases. In particular, there was a profound upregulation of various matrix metalloproteinase (MMP) members including collagenases (MMP-1/13), MMP-9 and MMP-7. Toll-like receptors (TLRs) 4 and 2 were also shown to be upregulated. Increased transcription of genes encoding TLRs 2 and 4, lipopolysaccharide ligands, prostaglandin synthesis enzymes and MMPs have similarly been demonstrated in pyometra uteri in other studies (Chu et al. 2002; Silva et al. 2010; Chotimanukul and Sirivaidyapong 2011). A large number (>700) of genes were shown to be downregulated in the uteri of dogs with pyometra including a number of homeobox and zinc finger genes (Hagman et al. 2009). More knowledge of the complex local and systemic inflammatory response may allow identification of novel disease biomarkers or future targets for treatment.

Table 1. Eight genes that were the most (>100-fold) upregulated in the uterine tissue of four female dogs with pyometra compared to in the uterine tissue of four healthy dogs are illustrated (Hagman et al. 2009)
Title of upregulated geneGene symbolFold changep-value
  1. Additionally, 10 selected upregulated (>10-fold) genes associated with products or similar products that have been detected systemically in dogs diagnosed with pyometra are shown.

Secretory leucocyte peptidase inhibitorSLPI344.80.0006
Interleukin 8IL8242.90.0003
Sphingomyelin phosphodiesterase acid-like 3ASMPDL3A194.40.0002
S100 calcium-binding protein A9S100A9160.70.0002
Interferon-induced transmembrane protein 2IFITM2137.30.0002
Similar to Ig lambda chain V region precursorLOC612066129.50.0018
Similar to Ig kappa chain C region, B alleleLOC475754124.80.0053
Insulin-like growth factor–binding protein 1IGFBP1104.40.0004
Prostaglandin endoperoxide synthase 2PTGS288.70.0017
Serum amyloid A protein/serum amyloid A1SAA165.90.0031
Haptoglobin-related proteinHPR56.10.0025
Matrix metallopeptidase 1MMP144.70.0139
Matrix metallopeptidase 9 (gelatinase B)MMP929.40.0001
Interleukin 1 receptor, type IIIL1R219.70.0024
Interleukin 6 (interferon, beta 2)IL617.80.0324
Serum amyloid A1SAA112.30.0162
Matrix metallopeptidase 13 (collagenase 3)MMP1312.10.0016
Interleukin 18-binding proteinIL18BP11.10.0012

Future Management Strategies for Pyometra

  1. Top of page
  2. Contents
  3. Introduction
  4. Risk Factors
  5. Aetiology and Pathogenesis
  6. Case History, Clinical Signs, Diagnosis and Treatment
  7. Laboratory Findings
  8. Differentiation of Pyometra and Mucometra
  9. The Local Uterine Inflammatory Response
  10. Future Management Strategies for Pyometra
  11. References

Early diagnosis and therapeutic intervention may prevent severe complications associated with advancing sepsis in dogs with pyometra. For this purpose, it is crucial to identify diagnostic or prognostic biomarkers that can be used in clinical practice. To be able to detect and evaluate suitable biomarkers, it is necessary to obtain more knowledge of the aetiology, pathogenesis and systemic development of the disease. In the long-term perspective, preventive measures for pyometra need to be explored. Development of a vaccine aimed at certain virulence attributes of bacteria associated with pyometra could be applicable for susceptible individuals. A genetic predisposition for the disease might, if identified, provide the possibility of implementing breeding programs aimed at reducing the occurrence in high-risk breeds. Prevention of pyometra by elective neutering has the advantage of surgery being performed in a healthy individual, but unwanted side effects of the procedure occur. Possible health benefits of neutering will need further investigation because of large breed variations.

Conflicts of interest

None of the authors have any conflicts of interest to declare.

Author contributions

R. Hagman is the sole contributor for this paper.

References

  1. Top of page
  2. Contents
  3. Introduction
  4. Risk Factors
  5. Aetiology and Pathogenesis
  6. Case History, Clinical Signs, Diagnosis and Treatment
  7. Laboratory Findings
  8. Differentiation of Pyometra and Mucometra
  9. The Local Uterine Inflammatory Response
  10. Future Management Strategies for Pyometra
  11. References
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  • Chu PY, Salamonsen LA, Lee CS, Wright PJ, 2002: Matrix metalloproteinases (MMPs) in the endometrium of bitches. Reproduction 123, 467477.
  • Dabrowski R, Kostro K, Lisiecka U, Szczubiał M, Krakowski L, 2009: Usefulness of C-reactive protein, serum amyloid A component, and haptoglobin determinations in bitches with pyometra for monitoring early post-ovariohysterectomy complications. Theriogenology 72, 471476.
  • Egenvall A, Hagman R, Bonnett BN, Hedhammar A, Olson P, Lagerstedt AS, 2001: Breed risk of pyometra in insured dogs in Sweden. J Vet Intern Med 15, 530538.
  • Fransson BA, 2003: Systemic Inflammatory Response in Canine Pyometra. Doctoral Thesis. Acta Universitatis Agriculturae Sueciae, Veterinaria 161, pp. 48.
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  • Silva E, Leitão S, Henriques S, Kowalewski MP, Hoffmann B, Ferreira-Dias G, da Costa LL, Mateus L, 2010: Gene transcription of TLR2, TLR4, LPS ligands and prostaglandin synthesis enzymes are up-regulated in canine uteri with cystic endometrial hyperplasia-pyometra complex. J Reprod Immunol 84, 6674.