Diagnosing Inflammatory In The Dog And Cat Bowel Disease

Dr Martin de Scally

BVSc, Hons MMedVet (Med) Small Animals (Pret)

Hilton Veterinary Hospital

e-mail: martin@hiltonvethospital.co.za

Tel: 0333434602 | Fax: 0333431021

Canine and feline inflammatory bowel disease (IBD) is a chronic (> 3 weeks), idiopathic, inflammatory enteropathy. These idiopathic inflammatory changes may respond to immunosuppression but it is vital to rule out all known causes before calling the disease idiopathic.

Introduction and description

IBD is currently under intensive investigation. With evolving theories of pathogenesis, aetiologies and treatment, IBD will probably continue to be redefined. As an example, histopathological findings together with new technologies such as 16sRNA pyro-sequencing and fluorescent in situ hybridisation (FISH) and candidate gene sequencing have helped clarify certain previously idiopathic diseases that were incorporated under the IBD umbrella. Granulomatous colitis (GC) and Histiocytic ulcerative colitis (HUC) seen in Boxers and French Bulldogs is now known to be highly associated with attached invasive Escherichia coli (AIEC); these cases have a long term response to fluoroquinolone antimicrobials and do not respond well to immunosuppressive therapy.

Classification

Traditionally IBD has been classified histologically according to the type of inflammatory cell infiltration and the site of inflammation, for example lympho-plasmacytic enteritis or granulomatous colitis. Secondary changes in the intestinal mucosa including, villous atrophy, fusion of villi, fibrosis, lacteal dilation and crypt changes are considered important in characterising the significance of these infiltrates. IBD can be clinically classified into food responsive enteropathies (FRE), antibiotic responsive enteropathies (ARE) and idiopathic IBD.

A GAME CHANGER

Granulomatous colitis (GC) and Histiocytic ulcerative colitis (HUC) seen in Boxers and French Bulldogs is now known to be highly associated with attached invasive Escherichia coli (AIEC); these cases have a long term response to fluoroquinolone antimicrobials and do not respond well to immunosuppressive therapy.

Clinical Signs

The clinical signs of (IBD) are similar to other chronic enteropathies (CE) and are determined by the site, extent, chronicity and severity of disease. Vomiting, for example, may reflect upper gastro-intestinal involvement; large volume diarrhoea, depression, melena, anorexia and ascites and other severe systemic signs may indicate small intestinal involvement; and small volume frequent stools with tenesmus and mucus or haematochezia may indicate colonic disease. Patients may also have a diffuse disease distribution.

The clinical signs may fluctuate in severity over time and overlap with many other organ diseases such as Addison’s disease, hepatic and pancreatic diseases. Clinical signs are therefore broad spectrum and non-pathognomonic but usually strongly indicative of intestinal involvement.

Pathogenesis

The pathogenesis of IBD is unknown. Current theories include hypersensitivities as a result of immune system dysregulation and loss of tolerance to luminal antigens; pathological events increasing mucosal barrier permeability and exposing previously privileged innate immune system receptors to luminal commensals and dietary components; genetic mucousal innate immune system derangements predisposing the host to invasion by its own microbiota; loss of inflammatory cell apoptosis; food intolerance or other nutrition induced host microbiota dysbiosis and host microbiota mutations.

Diagnosis

Diagnosis of IBD requires that systematic elimination process is followed.

Clinical examination

A clinical examination always includes signalment, history, hands off examination and physical examination. It is used to localise the patient’s disease to at least include the intestine, determines the chronicity (> 3 weeks), and determines the distribution and severity of the disease. The severity of the disease and the detection of extra-intestinal clinical signs determine the urgency and extent of diagnostic investigations and therapeutic intervention. For example severe IBD may cause protein losing enteropathy (PLE) with consequential loss of muscle condition score, body condition score, development of hypoproteinemia and cavity effusions; these patients need to be aggressively worked-up and treated. Other patients may have relatively mild clinical signs without weight loss or debilitation allowing a progressive methodical work up which may include empirical treatment for parasites, a therapeutic dietary intervention and an empirical antibiotic trial.

A minimum database for potential IBD patients

The first diagnostic challenge faced is ruling out primary intestinal pathogens, extra-intestinal disease, and concomitant diseases. A complete blood count (CBC), serum chemistry profile, urine analysis, and multiple faecal wet preparations and faecal flotations, are recommended in all cases to help rule out extra-intestinal disease and to help establish the severity of the intestinal disease.

An extended database selected for individual IBD patients

Faecal α1-protease inhibitor is useful to document PLE in untreated canine IBD cases. Faecal culture may be useful for the detection of salmonellosis or campylobacteriosis in some severe cases; cultured E.coli is not significant unless they are determined to be attached invasive type, which can only be determined with highly specialised techniques.

Evaluation of serum cobalamin levels may be useful in cats and dogs with IBD to help guide replacement therapy; it is also low in cats with lymphoma and pancreatic disease. Clinically significant hypocalcaemia and hypomagnesemia has been reported in cases of PLE in Yorkshire Terriers. Canine and feline pancreatic lipase immunoassay may be useful to help rule out pancreatitis in selected cases. A canine trypsin-like immunoassay (TLI) is used to rule out exocrine pancreatic insufficiency (EPI), especially in German Shepherd dogs (GSDs). Dogs with concurrent EPI and IBD have severe weight loss and may exhibit coprophagia and an increased appetite in addition to typical IBD signs. Thyroid hormone levels and FIV and FeLV status should be known in cats.

Radiography and ultrasonography are useful to detect extra-intestinal disease, intestinal obstruction as well as to help define intestinal disease. As the work up evolves, endoscopy or laparoscopy/laparotomy procedures are conducted. In severe cases they are ordered immediately.

Stepwise work up of non-critical patients with symptoms of IBD

What follows is a step wise approach that attempts to encompass the many clinical variations seen in practice.

1. Rule out intestinal helminths and protozoal infections

It is considered standard practice to thoroughly screen all dogs and cats with a CE for helminths and protozoa multiple times (at least 3X) very early in the diagnostic work up. Faecal tests for giardia can be supplemented by a faecal ELISA that is highly sensitive and specific. It is also considered standard practice to empirically treat for helminths and protozoa even if the screening tests are negative.

Giardia has variable therapeutic sensitivities. Possible treatments are metronidazole, febantyl and fenbendazole. Success of therapy should be reassessed with appropriate tests. In cases resistant to treatment environment, therapeutic sensitivity and a genetic immunopathology which may predispose the patient to infection are considered. In these cases drug combinations are used together with a high fibre diet and environmental decontamination.

In cats especially, Pentatrichomonas spp and Tritrichomonas spp must also be considered. These parasites can be seen on faecal wet prep mounts, diagnosed on faecal polymer PCR or in the case of Trichomonas spp cultured from faeces using the bovine TTF culture medium. Tritrichomonas is treated with ronidazole. Spontaneous remissions do occur and an asymptomatic carrier state is recognised. Ronidazole resistance has also been encountered.

Other more obscure intestinal pathogens, for example Cryptosporidium spp, Histoplasma spp., Toxoplasma spp., Mycobacteria spp., Protothecosis and Pythiosis may only be diagnosed cytologically or on histopathology if the work up is pursued.

2. Rule out Food Responsive Enteropathy (FRE)

Before conducting a diet trial the severity of the disease should be established. A canine inflammatory bowel disease activity index (CIBDAI) or a canine chronic enteropathy clinical activity index (CCECAI) index in the dog and a feline inflammatory bowel disease activity index (FIBDAI) in the cat is established. Some authors advocate the addition of an albumin value and histological score to the CIBDAI activity index. Whilst this may be necessary in individual cases, and in research, the practicality of repeat endoscopic procedures in clinical practice is limited.

Interpretation of index score

The FIBDAI is not graded as it is in the dog and does not differentiate food responsive enteropathy (FRE) from idiopathic IBD cases. The numeric number is simply used as a reference for evaluating post treatment success which is set 75% of the original pre-treatment score. A good response to a therapeutic trial is seen as a CCECAI score reduction from mild to moderate disease down to insignificant disease in dogs; and a FIBDAI score reduction from 5 to 9 down to 0 in cats. By definition a 75% reduction in FIBDAI score is considered positive.

Table 1: The CIBDAI & CCECAI Indices

Parameter

Clinical Inflammatory Bowel Disease Activity Index (CIBDAI)

Canine Chronic Enteropathy Clinical Activity Index (CCECAI)

Attitude/Activity

0 – normal

1 – slightly decreased

2 – moderately decreased

3 – severely decreased

0 – normal

1 – slightly decreased

2 – moderately decreased

3 – severely decreased

Appetite

0 – normal

1 – slightly decreased

2 – moderately decreased

3 – severely decreased

0 – normal

1 – slightly decreased

2 – moderately decreased

3 – severely decreased

Vomiting

0 – normal

1 – mild (1x/wk)

2 – moderate (2-3x/wk)

3 – severe (>3x/wk)

0 – normal

1 – mild (1x/wk)

2 – moderate (2-3x/wk)

3 – severe (>3x/wk)

Stool consistency

0 – normal

1 – slightly soft

2 – very soft

3 – watery diarrhoea

0 – normal

1 – slightly soft

2 – very soft

3 – watery diarrhoea

Stool (or mucus/

blood) Frequency

0 – normal

1 – slightly increased (2-3x/d)

2 –moderately increased (4-5x/d)

3 – severely increased (>5x/d)

0 – normal

1 – slightly increased (2-3x/d)

2 –moderately increased (4-5x/d)

3 – severely increased (>5x/d)

Weight loss

0 – none

1 – mild (<5%)

2 – moderate (5 – 10%)

3 – severe (>10%)

0 – none

1 – mild (<5%)

2 – moderate (5 – 10%)

3 – severe (>10%)

Albumin levels

0 –albumin >20g/L

1 – albumin 15 – 19g/L

2 – albumin 12 – 14g/L

3 – albumin <12g/L

Ascites and

peripheral oedema

0 – none

1 – mild

2 – moderate

3 – severe (possible pleural effusion)

Pruritis

0 – no pruritis

1 – occasional itching

2 – regular itching, stops if sleeping

3 – wakes up to scratch

 

Interpretation of index score

CIBDAI

0 – 3

4 – 5

6 – 8

> 9 ( 18)

Clinically insignificant

Mild disease

Moderate disease

Severe disease

 

CCECAI

0 – 3

4 – 5

6 – 8

9 – 11

> 12 (24)

Clinically insignificant

Mild disease

Moderate disease

Severe disease

Very severe disease

 

A well conducted food diet trial will solve both dietary hypersensitivities and food intolerances; both of which can cause IBD symptoms. Most clinical trials see a high percentage of patients responding to diet. Canine patients with lower CIBDAI or CCECAI scores (<5) and clinical signs associated with diffuse lower intestine disease are more likely to respond to dietary therapy than those with very high (>5) CIBDAI or CCECAI scores. No such predictions can be made using the FIBDAI score in cats.

Dietary hypersensitivities are immunological reactions to dietary antigens and dietary intolerances are non-immunological reactions to perturbations within the diet itself. For this reason some animals will respond to highly digestible, fat restricted and variable fibre diets that do not have any antigenic modifications. Usually single protein diets, containing a highly digestible novel protein source or hydrolysed diets are used. Size and structure of dietary proteins appears to affect their potential for immunoreactivity.

The role of the immune system and host microbiota in dietary hypersensitivities are being investigated. Perinuclear anti-neutrophilic cytoplasmic antibodies (pANCA) were significantly higher in diet responders than idiopathic IBD patients in one study but the clinical usefulness has not been established. Skin reactions are usually only seen with dietary hypersensitivity.

In the case of hydrolysed diets, potential problems include palatability issues and molecule sizes that still evoke an immune response. A complete dietary history is necessary to select the protein and carbohydrate sources in an elimination diet to suit that patient. Dietary history forms are available on the WSAVA website. Immediate, Type I and II, as well as delayed, Type IV hypersensitivities are possible with dietary antigens.

Establishing cause and effect in these cases requires strict owner compliance. Response to diet may occur within 10 to 15 days or as long as 8 to 12 weeks. Canine diet responders have an excellent prognosis but complete responders should undergo a re-challenge after 3 months because most of these patients remain asymptomatic on a fresh supply of their original type of food. The reason for this is unknown but may be related to dietary intolerances or dietary induced changes in the resident microbiome of the patient rather than dietary hypersensitivities. Unfortunately some references document a poor response to diet in cats and others warn that many initial responders may relapse and go on to require immunosuppressive therapy. For a diet trial to work the patients must be eating; appetite stimulants may be helpful in some anorexic cases.

Dietary hypersensitivities are immunological reactions to dietary antigens and dietary intolerances are non-immunological reactions to perturbations within the diet itself.

3. Conduct an empirical antibiotic trial in non-responders to exclude Antibiotic Responsive Enteritis (ARE)

Gastrointestinal dysbiosis is the new term describing unhealthy disturbances in the intestinal microbiota replacing the old term of small intestinal bacterial overgrowth (SIBO). There is currently no way of adequately and convincingly diagnosing bacterial dysbiosis in a clinical situation short of a therapeutic trial; for this reason the condition is recognised as an antibiotic responsive enteropathy (ARE).

Antibiotics empirically used include amoxicillin, metronidazole, oxytetracyclines, sulfasalazine and tylosin. The choice of antibiotics depends on the clinician’s bias. Metronidazole is often advocated but potential carcinogenic side effects of long-term administration are a concern. Tylosin is well tolerated long term and may also treat occult cryptosporidium infection in some cases, it is also one of the few antibiotics besides fluoroquinolones, with some literature based evidence rationalising its use. Tylosin has activity against gram-positive and gram-negative cocci, gram-positive rods, and mycoplasma; it is not effective against Escherichia coli and Salmonella spp.

It is therefore not used as targeted therapy against specific bacterial enteritis but rather to transiently change the intestinal microbiota possibly by promoting the growth of beneficial commensal bacteria while suppressing deleterious bacteria. Starting dose is 15 mg/ kg PO BID mixed with the food or given via gelatine capsule.

Patients that do respond to antibiotics are categorised as having ARE. The use of fluoroquinolones is retained specifically for where AIEC are suspected. He duration of the antibiotic course is usually 1-2 weeks before patients are monitored for a relapse of clinical signs. Frequency and severity of relapses determine the need for continuous, intermittent regular or reactive only treatment.

The role of Helicobacter infection in IBD is not well defined. In one small study fluorescence in situ hybridisation techniques were used to diagnose the organism intraglandular in the epithelium, in the presence of gastritis. The same technique was used to show resolution after “triple therapy” and dietary therapy was instituted. Triple therapy is only recommended in those patients with clinical signs and histopathological evidence of gastritis in the presence of Helicobacter organisms.

4. Conduct a probiotic trial

In one study adding a probiotic cocktail to known FRE had no added benefit over diet therapy (Sauter et al 2006). In other studies a clear, safe benefit is suggested provided their use is continued (German et al 2010, Herstad et al 2010, Bybee et al 2011). It also may seem counterintuitive to give GI antibiotics with probiotics however clinical improvement is often seen when given in combination with each other.

In another study in non FRE relapsing chronic IBD cases probiotics (VSL#3 strains) significantly improved clinical and histological scores, decreased CD3+ T-cell infiltration, increased regulatory T-cell markers (FoxP3+ and TGF-β+) and normalised intestinal dysbiosis in dogs with IBD compared to a combination of prednisolone and metronidazole (Rossi et al 2014).

The dogs in this study treated with VSL#3 also showed significantly increased plasma citrulline indicating restoration of the mucosal barrier although this clinical parameter was not compared to the immunosuppressive treatment group (Dossin et al 2011). This finding is significant and warrants futher investigation. Probiotics are thought to have immunomodulatory effects and antimicrobial activities directed toward intestinal pathogens (Rath 2003). Recommendations are to use a product produced by a reputable veterinary company backed by research for at least 2 months.

5. Repeat an ultrasonographic examination

Ultrasonographic studies are used to document abdominal changes consistent with IBD, aid in endoscopic biopsy site selection and help to detect extra-intestinal disease and intestinal neoplasia. Hyperechoic mucosal striations are indicative of lacteal dilation in dogs.

Other common ultrasonographic findings associated with IBD include small intestinal wall thickening, hyperechoic mucosal speckles, abdominal effusion and mesenteric lymphadenopathy. Older cats with diffuse thickening of the muscularis layer of the intestine are more likely to have T-cell lymphoma than IBD. Lymphadenopathy is equally associated with both diseases. Fine needle aspiration can also be performed.

6. Conduct endoscopic and histopathological examinations

Endoscopy is increasingly the preferred method of obtaining samples in dogs as it is minimally invasive, widely available and allows direct visualisation of the gastrointestinal mucosa. Endoscopic examination, biopsy and histopathology, using the WSAVA gastroenterology standardisation group guidelines, are recommended for animals presenting with severe disease or those not responding to initial therapeutic trials. Inter-operator variation in endoscopic interpretation is reduced by the use of standardised endoscopy evaluation forms and standardised histopathological templates and criteria.

Plasma citrulline is considered a sensitive indicator of GIT permeability. (Dossin et al 2011)

Histopathology allows grading and typing of mucosal inflammation and secondary changes. Other causes of intestinal disease, including helicobacter gastritis, cryptosporidium enteritis and neoplasia, may also be diagnosed. Where possible the more difficult to reach ileum is also biopsied. The ileum consistently shows mucosal changes most commonly in most patients.

This is especially important in cats to avoid missing focal ileal disease and small cell lymphoma (SC-LSA). Some cases may require sampling of focal disease and submucosal diseases surgically – via laparoscopy or laparotomy as the diagnosis may be inconclusive in endoscopically derived samples.

Laparoscopy (laparotomy) is suggested as the preferred method of obtaining samples in the cat where early small cell intestinal lymphoma often requires differentiation from IBD, and commonly affected areas tend to be ileum and jejunum which are more difficult to sample endoscopically.

Despite this most cats with IBD are still biopsied endoscopically because it is minimally invasive, more available and cheaper and immunophenotypic staining and other tests can be used to help differentiate small cell lymphoma from IBD on endoscopic samples.

IBD has been traditionally classified according to the inflammatory cells predominantly infiltrating the intestinal mucosa and which part of the intestine is affected. Lymphocytic-plasmacytic enteritis is the most common type of IBD seen in small animals.

Other forms are varying populations of eosinophilic, neutrophilic, histiocytic (mainly PAS-positive macrophages) and granulomatous (mainly PAS-negative macrophages) mucousal infiltrates causing gastroenterocolitis in individual patients. Linking type of histological inflammation to various studies on the innate immune system and intestinal microbiota has led to some improvements been made in the treatment of IBD.

The reader is referred to the open publications available from the WSAVA gastroenterology standardisation group for a thorough discussion on the standardisation of endoscopic examinations, biopsy sampling techniques and histopathological interpretation of IBD cases; as well as standardised endoscopic and histopathology examination forms.

Other breed specific enteric disease are also reported in Boxers, French Bull Dogs, German Shepherd Dogs (GSDs), Sharpei’s, Yorkshire Terriers, Soft Coated Wheaten Terrier’s, Irish Setters, with their individual nuances.

Monitoring Response to Therapy

Follow up endoscopy and histopathology:

Although repeated IBD activity index scores are the most common way patients are monitored repeat endoscopic and histopathology studies have been regularly performed in academic/research studies. Improving IBD index scores is usually associated with an improved intestinal mucosal appearance endoscopically and improved intestinal mucosal integrity and, if specialised organism detecting techniques are used, with a decrease in mucosal adhesion and invasion of potential pathogens; but the actual lamina propria inflammatory cell numbers may not be decreased in these repeat biopsies.

One explanation for this may be decreased post event apoptosis of the resident lymphocyte populations another may be continued unresolved underlying perturbations.

Selected references in text

• Sauter, S.N. et al (2006) Effects of probiotic bacteria in dogs with food responsive diarrhoea treated with an elimination diet. J Anim Physiol Anim Nutr 90:269–277

• German, A.J., et al (2010) First-choice therapy for dogs presenting with diarrhoea in clinical practice. Vet Rec 21:810

• Herstad, H.K. et al (2010) Effects of a probiotic intervention in acute canine gastroenteritis–a controlled clinical trial. J Small Anim Pract 51:34

• Bybee, et al (2011) Effect of the probiotic Enterococcus faecium SF68 on presence of diarrhea in cats and dogs housed in an animal shelter. J Vet Intern Med 25:856

• Dossin, O. et al (2011) Effect of Parvoviral Enteritis on Plasma Citrulline Concentration in Dogs. J Vet Intern Med 25: 215–221

• Rath, H.C. (2003) The role of endogenous bacterial flora: bystander or the necessary prerequisite? Eur J Gastroenterol Hepatol 15:615–620

• Rossi, G. et al (2014) Comparison of Microbiological, Histological, and Immunomodulatory Parameters in Response to Treatment with Either Combination Therapy with Prednisone and Metronidazole or Probiotic VSL#3 Strains in Dogs with Idiopathic Inflammatory Bowel Disease. PLoS ONE 9:e94699. doi:10.1371/journal.pone.0094699

Remainder of references available on www.vet360. vetlink.co.za

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