Canine Cystic Endometrial Hyperplasia-Pyometra Complex

Definition

Pyometra is a serious, life-threatening infection that occurs when the uterus fills with pus due to endometritis (endometrium inflammation), metritis (myometrium inflammation), and cystic endometrial hyperplasia (CEH) that occur in response to estrogen-induced endogenous luteal ovarian progesterone or exogenous progesterone, and a secondary bacterial infection (purulent endometritis), causing systemic changes.

Introduction

Pyometra is driven by hormonal shifts and frequently involves the gram-negative bacteria, E. coli.

It typically occurs during estrus (when the intact female dog is in heat), at which time the cervix is open and relaxed. 

The cervix is closed most of the time, but during estrus, the cervix opens up and relaxes in order to allow sperm to enter the uterus. During this time, bacteria can more easily travel from the vagina and enter the uterus. This is the reason pyometra often manifests one to two months post-heat, during diestrus. During diestrus, elevated progesterone levels cause the uterine lining to thicken. Over several cycles, this can lead to CEH, where cysts form and secrete fluids that encourage bacterial proliferation.

As the uterus accumulates bacteria and pus, harmful toxins can enter the bloodstream, resulting in a critical condition.

Incidence

CEH-pyometra complex is the most common uterine disorder of intact female dogs. The incidence in intact female dogs by the time they reach 10 years of age is 3 to 66% (average 19 to 25%).

Signalment

Affected dogs range from 6 months to 18 years of age, averaging 8 to 9.36 years of age. Most present within 8 weeks of their last estrus. Nulliparous bitches are more common than multiparous and primiparous bitches.

Etiology

Causes include hormonal influences/imbalances (most common and influential), having an open cervix (postpartum bacterial infiltration post-breeding), structural changes (retained fetal/placental tissues, obstetrical manipulations, and infectious abortions), dietary (intestinal colonization by E. coli strains), genetic influences (Golden Retrievers and the ABCC4 gene), aberrant immune responses, and metabolic dysregulation (lipid metabolism, oxidative stress).

Hormonal Influences or Imbalances

The canine reproductive cycle involves prolonged phases of hormonal activity, making the endometrial tissue vulnerable to degenerative changes. Estrus promotes uterine cell growth, endometrial vascularization, and uterine sensitivity/response to progesterone. Hormonal imbalances or an abnormal response to the normal concentration of estrogen/progesterone alters uterine epithelial cells, facilitating bacterial adherence, colonization, and growth. CEH-pyometra usually occurs in the early or first half of the diestrus phase (15% incidence). However, pregnancy and the luteal phase itself may be involved.

Pathophysiology

Increased progesterone concentrations causes endometrial growth, glandular proliferation, glandular secretions (mucoid, serous, or bloody fluid accumulates leading to fluid-filled cysts), cervical closure, neutrophil phagocytosis, chemotaxis inhibition, and bacterial adherence. The effects of progesterone include endometrial proliferation, increased endometrial glandular secretion (allowing bacterial growth), cervix closure (inhibiting drainage), myometrial contraction inhibition (inhibiting drainage), and a decrease in mononuclear cellular response (modulating T-cell action and suppressing the local cellular immune response). Progesterone causes disruption of the endometrial epithelium, exposing the uterus to bacteria and bacterial products, increasing the infection risk. Defective bacterial clearance occurs due to an abnormal uterine response to these ovarian hormones. Infection and secondary septicemia/endotoxemia occurs.

CEH-Pyometra Complex Types

Pyometra may be associated with acute or chronic polycystic disease, and acute or chronic endometritis. CEH and pyometra can occur independent of each other or CEH may lead to pyometra.

Type I: CEH, a thickening of the tissue, thin-walled/translucent cysts

Type II: Progesterone accumulation causes cervical relaxation/patency

Type III: Plasma cells accumulation, acute inflammation and clinical signs

Type IV: Chronic endometritis with an open or closed cervix

A: Open cervix, large uterus (up to 3 cm in diameter) with endometrial fibrous changes, hypertrophy, cysts

B: Closed cervix, large uterus, thin-walled/atrophic cysts

Sepsis and Systemic Inflammatory Response Syndrome

Early detection and treatment of sepsis and systemic inflammatory response syndrome (SIRS) is essential, but accurate diagnosis is challenging due to its complexity and lack of specific biomarkers. Inflammatory mediators are induced in response to endotoxin (lipopolysaccharide/LPS) released by Gram-negative bacteria during their growth or death.

Septic Secondary Peritonitis

Septic peritonitis (8.6 to 10.2%) can occur due to perforation of the infected or gravid uterus (58%, from pregnancy, trauma, spontaneously, or iatrogenic), transmural uterine wall spread, and bacterial passage from the uterine lumen via the uterine tube (due to myometrial contractions towards the ovarian bursa, subsequently into the peritoneal cavity).

Closed- versus Open-Cervix Pyometra

Closed-cervix pyometra (23 to 35% incidence) lacks of purulent vaginal discharge. Open-cervix pyometra (40 to 73.3%) exhibits vaginal discharge. Vaginal discharge varies as the cervix will alternate between opening and closing.

Moderate or severe depression is seen in 30% with open- and 56% with closed-cervix pyometra. Leukocytosis, neutrophilia, monocytosis, and a moderately to severely depressed general condition occurs more with closed versus open. Sepsis is more common in closed (77%) versus open (51%). Postoperative hospitalization length does not differ.

Clinical Signs

Note that the presentation of clinical signs are affected by whether the cervix remains open or closes.

Clinical signs include: none (66 to 70% incidence, enlarged uterus incidentally detected during checkups), vaginal discharge (50 to 85%), vomiting or anorexia (75%), vomiting alone (21.1 to 27%), depression (36 to 98%), non-ambulation (88%), obtundation or lateral recumbency (62%), anorexia alone (10 to 69%), polyuria-polydipsia (20 to 70%), lethargy (20 to 70%), lameness (16.4%), and diarrhea (14 to 15.4%).

Two to three clinical signs are in 60% of cases.

The duration of clinical signs before diagnosis ranges from 0 to 45 days with most being 15 days, typically within several weeks of their last estrus.

Physical Examination Findings

Abnormalities include: abdominal pain (22.7 to 75% incidence), cystitis (70%), enlarged uterus on abdominal palpation (18.8%), dehydration (26.4 to 50%), SIRS (57 to 74%), febrile (20 to 42%), hypothermia (4%), hyperemic mucous membranes (8 to 16.3%), any combination of tachypnea, tachycardia, or pallor (20 to 30%), and pallor alone (16.3%).

On clinical examination, pyometra was diagnosed in 64.5%, while 57.5% had open- and 42.5% had closed-cervix pyometra.

Biochemistry Profile

1. Hypoalbuminemia; 81% of cases with hyperglobulinemia (acute phase reaction), and hyperproteinemia
2. Hyperbilirubinemia, hypercholesterolemia, elevated alkaline phosphatase (37%), elevated aspartate aminotransferase, elevated lactate dehydrogenase, elevated bile acids (23.3%), elevated alanine aminotransferase
3. Hyperglycemia (3.8%), hypoglycemia (4.5%)
4. Acidemia, respiratory alkalosis
5. Elevated blood urea nitrogen concentration (6.5%), increased creatinine (4.8%), azotemia (6 to 30%)
6. Glomerular damage (75% have proteinuria), decreased glomerular filtration rate (GFR), elevated urinary gamma-glutamyl transpeptidase, elevated N-acetyl-β-D-glucosamine; the latter two are seen in 25% of dogs. The decreased GFR results in azotemia, due to immune complex deposition, and renal tubule changes. Acute kidney injury is from systemic infection (57% due to hypoperfusion, 22% due to inflammation)
7. Decreased urine specific gravity; 75% have proteinuria (decreased renal function from E.coli-induced endotoxin interacting with the distal convoluted tubules or collecting ducts resulting in inhibition of the anti-diuretic hormone response); renal alterations resolve months post-operatively

Complete Blood Count (CBC)

1. Inflammatory leukogram (leukocytosis, 37 to 54.3% of cases), regenerative left shift,
   neutrophilia (55.3%), and monocytosis (50.7%)
2. Leukopenia (3.6% incidence), neutropenia (3.7%), either neutrophilia or neutropenia (58%),
   monocytopenia (3.3%), and lymphopenia
3. Toxic neutrophils; 9.4%
4. Band neutrophils; 3 to 83%
5. Normocytic, normochromic anemia (59.7%), thrombocytopenia (40%)

Plain Abdominal Radiography

Images may show: enlarged uterus (low specificity/sensitivity), homogenous tubular structure of
fluid density in the caudal abdomen, retained feti, and gas-filled tubular structures in the right
and left caudal abdomen (emphysematous pyometra).

Abdominal Ultrasonography (AUS)

1. Uterine fluid; purulent (38%), mucous (19%), and serous (42.9%)
2. Abnormal uterine wall thickness
3. Uterine cystic changes
4. Increased uterine luminal diameter; 29 mm
5. Hyperechoic feti
6. Endometrial gland hyperplasia; 1 to 2 anechoic uterine areas
7. Emphysematous pyometra

Cardiac Diagnostics

1. At least one arrhythmia; 79.4%
2. Sinus tachycardia; 56.4%
3. Ventricular premature complexes; 23%
4. Increased amplitude of T wave; 17.9%
5. ST depression; 10.2%
6. Second-degree atrioventricular block; 5.1%
7. Increase of QT interval; 5.1%
8. Sinus bradycardia; 5.1%
9. First-degree atrioventricular block; 2.5%
10. Low wave amplitude; 43.5%

Uterine Biopsy

Histopathological uteri examination show 17% have CEH, 50% moderate CEH-pyometra, and 33% severe CEH-pyometra.

Urine Culture/Sensitivity Testing

A concurrent urinary tract infection (UTI) is diagnosed in 5.6 % to over 70% of cases. The subclinical UTI incidence is 25%. During pyometra surgery, bacterial growth was detected in 87% of uterine specimens and concurrent bacteriuria in 33% of cases. E. coli is the most common isolate (50 to 100% incidence) in uterine (48 to 71%) and urine (20 to 81%) specimens.

A single species of bacteria is seen in 91.5% of cases, more than one species in 8.5%, two species in 60%, three species in 10%, and polybacterial infections in 30%. E.coli is always one of the species involved in polybacterial infections. Negative bacterial cultures are seen in 9 to 10% of cases.

Antimicrobial Susceptibility and Resistance

E. coli can exhibit resistance: piperacillin, amoxicillin-clavulanic acid, cefazolin, ceftazidime, cefepime, meropenem, amikacin, sulfamethoxazole-trimethoprim, lincomycin and cefotaxime.

Resistance to cephalosporins or ampicillin is in less than 10% and to enrofloxacin in 3% of cases. Of E. coli strains 72.1% exhibit resistance to third-generation cephalosporins and/or fluoroquinolones, and 24.6% are extended-spectrum ß-lactamase-producers. Susceptibility may be seen to aztreonam, minocycline, levofloxacin, and amikacin. Treatment may include doxycycline and orbifloxacin. Uterine and vaginal content found that 49.4% isolates were resistant to one or more drugs; Gram-positive bacteria resistance (87.5%) is more common than Gram-negative (32.7%).

Treatment

The treatment of choice for pyometra is (emergency) surgery. Medical treatment can be considered if the patient is not ill, vaginal drainage is occurring, the bitch has a high breeding value, for those in poor condition (due to age, anesthetic risks, co-morbidities, etc), those owners with financial limitations, and to improve patient status pre-operatively. Medical treatment is not indicated for those who are pyretic, hypothermic, have peritonitis, closed cervix, and with ovarian cysts/other concurrent intra-abdominal disease.

Medical treatment aims to decrease progesterone and increase uterine evacuation (ecbolics) via progesterone receptor antagonist therapy (aglepristone, mifepristone), prostaglandin F2α therapy (dinoprost, cloprostenol), gonadotropin-releasing hormone antagonist therapy (acyline), dopamine agonist therapy (cabergoline), or a combination. Antimicrobials are always used in conjunction. Regardless, surgical intervention remains the treatment of choice.

Surgical Treatment

The open ventral midline celiotomy is most often recommended and implemented. Preoperative considerations Iatrogenic septic abdomen risk decreases with preoperative/intraoperative cystocentesis,
avoidance of abdominal/urinary bladder palpation, and immediate surgery. Retrograde urinary catheter placement can be considered to improve surgical visualization.

Surgical Complications

Overall ovariohysterectomy complication incidence is 7.5 to 20%, increasing with those over 2 years of age, prolonged surgical time, and larger body weight. Complication odds increase by a factor of 1.03 for every one kilogram of weight increase. Complication odds increase by 2% for each additional anesthesia minute. Some complications include:

1. Ovarian remnant syndrome/stump pyometra
2. Respiratory; 16.3%
3. Hemorrhage; 3%, seen with those over 25 kg in weight and is the primary cause of death
4. Peritonitis
5. Incisional; 5 to 9%
6. Ureteral damage
7. Pancreatitis; 0.5%
8. Granuloma; less than 30% of uterine/ovarian pedicles with braided nonabsorbable suture
9. Fistula tract; ligature reaction, braided nonabsorbable or surgical gut suture
10. Urinary sphincter mechanism incontinence; 11 to 20%
11. Intestinal/urethral obstruction
12. Persistent polyuria-polydipsia/proteinuria; 12%
    Post-operative pyometra surgical complication incidence is 14 to 25%, associated with prolonged hospitalization in 10% of those cases that develop complications. Such complications include:
13. Sepsis/septic shock
14. Disseminated bacterial infection
15. Acute arterial thrombosis
16. Hemorrhage
17. Peritonitis; 12.5 to 13%
18. UTI; 5.3 to 6%
19. Wound infection; 2.2 to 3%
20. Uveitis; 1.7 to 2%
21. Cardiac arrhythmia; 1 to 1.4%
22. Persistent polyuria-polydipsia; 0.3%
23. Hepatic disease/ascites; 0.3%
24. Renal malfunction; 0.3%, E. coli in 8% of cases
25. Death; 1 to 17% incidence overall (0 to 27% in dogs), 5% within 3 years

General Outcome

Surgery is considered curative. Euthanasia mortality is 10 to 12.5%, uterine rupture mortality is 50% and peritonitis mortality is 3 to 12%. Clinics estimated that of the animals presented, 76% were BAR or QAR, 20% were depressed or non-ambulatory, and 4% were obtunded and lateral; estimated survival for these groups were 98%, 74 to 80%, and 31 to 38%, respectively.

Prognosticators

Overall 65% of dogs survive to discharge. The rate of survival to discharge is 97%; 44% stay in the hospital 2 nights or more, and 3% had a ruptured uterus. Prolonged hospitalization is associated with 19% morbidity.

1. High blood urea nitrogen (BUN) concentration; greater odds of death post-operatively
2. Heart murmur; greater odds of death post-operatively
3. Uterine rupture, inappetence, high concentrations of BUN or serum creatinine, low packed
   cell volume or dehydration; greater odds of hospitalization 2 or more nights
4. Hypoalbuminemia; negative prognosticator for sepsis survival
5. SIRS, pancreatic abscessation, septic abdomen; survival decreases
6. Prolonged hospitalization factors; moderate to severe depression (7-fold risk), pallor (3-fold
   risk), leukopenia (3.5-fold risk)
7. Hyperemic mucous membranes; decreased risk of prolonged hospitalization
8. Hyperlactatemia; prolonged hospitalization
9. Leukopenia; 18-fold risk of peritonitis, 3.5-fold risk of prolonged hospitalization
10. Normal white blood cells; risk of prolonged hospitalization/peritonitis versus leukocytosis
11. Who performs the surgery:
    Comparing referral hospitals and community clinics, survival to discharge is 97% and does not differ between them. Median duration between diagnosis and ovariohysterectomy is shorter at referral hospitals (0 days) versus community clinics (1 day); delay is not related to survival. Hospitalization duration does not impact survival to discharge or beyond. Private practices estimate that economic euthanasia is likely for 13% of patients; 80% are reluctant to refer to a high-quality, high-volume spay-neuter clinic because of lack of prompt appointment availability (20%), aftercare (18%), and equipment (14%).

Prevention

Surgical sterilization via ovariohysterectomy/ovariectomy is preventative.

Should signs of estrus or pyometra/stump pyometra occur post-preventative surgery, rule-out ovarian remnant syndrome, ectopic ovarian tissue, exogenous progesterone/estrogen administration, endocrine system neoplasia, or unethical veterinarian behavior.

Financial Expense

The majority (56%) of clients reported sometimes having trouble paying for all recommended
services, and others often (31%) or rarely (13%) have financial trouble.

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