J Vet Intern Med 2007;21:700–708
Chronic Enteropathies in Dogs: Evaluation of Risk Factors for Negative Outcome K. Allenspach, B. Wieland, A. Gro¨ne, and F. Gaschen Hypothesis: Certain variables that are routinely measured during the diagnostic evaluation of dogs with chronic enteropathies will be predictive for outcome and a new clinical disease activity index incorporating these variables can be applied to predict outcome of disease. Animals: Seventy dogs were entered into a sequential treatment trial with elimination diet (FR, food-responsive group) followed by immunosuppressive treatment with steroids if no response was seen with the dietary trial alone (ST, steroidtreatment group). A 3rd group consisted of dogs with panhypoproteinemia and ascites (PLE, protein-losing enteropathy) that were treated with immunosuppressive doses of steroids. Methods: Three years of follow-up information was available for all dogs. Clinicopathologic variables were tested for their ability to predict negative outcome, defined as euthanasia due to refractoriness to treatment. Different scoring systems including different combinations of these variables were evaluated using receiver operating characteristic (ROC) curves. Results: Thirteen of 70 (18%) dogs were euthanized because of intractable disease. Univariate analysis identified a high clinical activity index, high endoscopic score in the duodenum, hypocobalaminemia (,200 ng/L) and hypoalbuminemia (,20 g/L) as risk factors for negative outcome. Conclusions and clinical importance: Based on the factors identified by logistic regression and ROC curve analysis, a new clinical scoring index (CCECAI) was defined that predicts negative outcome in dogs suffering from chronic enteropathies. Key words: Canine; Chronic Diarrhea; Clinicopathologic variables; Prognosis.
mong the causes for chronic enteropathies (CE) in dogs, adverse reaction to food, idiopathic inflammatory bowel disease (IBD), and antibiotic-responsive diarrhea (ARD) are common.1–4 These disorders are diagnosed retrospectively by their response to treatment. Little information is available on clinical and clinicopathologic markers that may help distinguish between cases that respond to diet alone and those that require treatment with corticosteroids. Furthermore, little information is available on risk factors associated with refractoriness to treatment leading to euthanasia of affected animals.5 The purpose of this prospective study therefore was to evaluate standard tests performed during diagnostic evaluation of CE cases for their accuracy to predict response to therapy and outcome. Specifically, clinical signs, CBC, serum biochemical analysis, serum co-
A
From the Small Animal Teaching Hospital of the University of Bern, Department of Veterinary Clinical Medicine, Vetsuisse Faculty, Switzerland (Allenspach, Gro¨ne, Gaschen); and the Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, North Mymms, UK (Wieland). Dr Karin Allenspach is currently affiliated with the Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, North Mymms, UK. Dr Andrea Gro¨ne is currently affiliated with the Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. Dr Frederic Gaschen is currently affiliated with the Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA. This study was presented in part at the ACVIM Forum 2006 in Louisville, KY. May 31-June 3. Reprint requests: Karin Allenspach DVM., Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, Hawkshead Lane, North Mymms, Hatfield, AL9 7TA; e-mail: kallenspach@rvc.ac.uk. Submitted August 16, 2006; Revised October 18, 2006 and November 17, 2006; Accepted January 22, 2006 Copyright E 2007 by the American College of Veterinary Internal Medicine 0891-6640/07/2104-0004/$3.00/0
balamin and folate concentrations, 2-dimensional transabdominal ultrasound, endoscopy, and histopathology were evaluated for their usefulness to predict outcome. This study was part of a larger study with the broad goal of investigating the pathogenesis and treatment of CE in dogs performed at the University of Bern between 2002 and 2005. We aimed additionally to assess previously proposed markers of disease (ie, albumin5 and Creactive protein [CRP]6) for their effectiveness to predict response to treatment and outcome. We carried out a prospective study design and obtained objective data on clinical variables by using a previously published clinical scoring system (CIBDAI, canine IBD activity index),6 endoscopic scoring, and histologic scoring before and after a standardized treatment regimen.
Materials and Methods Over the 3-year period, 78 dogs with signs of chronic gastrointestinal disease were referred to the Small Animal Teaching Hospital, Vetsuisse Faculty, University of Bern, Switzerland. Four dogs were excluded because of intestinal neoplasia (2 lymphoma, 1 colonic adenocarcinoma, and 1 intestinal histiocytic sarcoma). Four dogs tested positive for Campylobacter spp. on fecal culture and had clinical signs consistent with acute campylobacter infection. In all other dogs, fecal culture results were negative for Campylobacter spp., Salmonella spp., Yersinia spp., and enteropathogenic Escherichia coli. The 4 dogs with positive cultures for Campylobacter spp. were successfully treated with erythromycin (15 mg/kg PO q8h for 4 weeks) and were excluded from the study. Seventy dogs were included in the prospective treatment trial. Some information about the clinical signs in 35 of the dogs in this study has been published elsewhere.7 Follow-up information was available for all 70 dogs during a period of 3 years after finishing the treatment trial. Owners of dogs were contacted every month by telephone and the dogs were re-examined if their clinical signs were worsening at any time point. Selection criteria for cases included a history of chronic diarrhea with or without vomiting of at least 6 weeks duration, exclusion of identifiable underlying disorders, and histopathologic evidence of intestinal inflammatory cellular infiltrates. None of the dogs had been treated with antibiotics, corticosteroids, or antacids in the 2 weeks before entering the
Risk Factors in Canine IBD study. Owners of dogs signed a letter of consent in which they agreed to participate in initial and follow-up diagnostic evaluation. All experimental procedures were approved by the Cantonal Committee in charge of Animal Experimentation, Bern, Switzerland and by the Ethical Committee of the Vetsuisse Faculty, University of Bern, Switzerland. All dogs received treatment with fenbendazole (50 mg/kg daily for 5 days) before being referred. Diagnostic tests performed to exclude underlying disorders included CBC, serum biochemical analysis, urinalysis, and analysis of fecal samples for parasites and bacteria including examination for endoparasitic ova and Giardia spp. by using direct smear evaluation and zinc sulfate centrifugal flotation techniques. Additional tests included assessment of serum concentration of trypsin-like immunoreactivity (TLI measured by radioimmunoassay [RIA] specific for dogs) and measurements of serum cobalamin and folate concentrations (both performed at the Laboratory of the Royal Veterinary College, London, UK), measurements of C-reactive protein concentrations (CRP, measured at the Texas GI Laboratorya), as well as 2-dimensional transabdominal ultrasound examination. No underlying infectious, pancreatic, or neoplastic disease was identified in any of the dogs. Dogs were classified according to their predominant clinical signs as having upper gastrointestinal disease with clinical signs such as anorexia, weight loss, melena, increased fecal volume, normal fecal frequency, or predominantly lower gastrointestinal disease, with signs such as mucus, hematochezia, tenesmus, increased frequency of defecation, and decreased fecal volume. All dogs were given a clinical score using the CIBDAI scoring system established by Jergens et al,6 which is based on 6 gastrointestinal variables that are routinely evaluated in affected dogs: attitude and activity, appetite, vomiting, stool consistency, stool frequency, and weight loss. After summation, the total composite score is determined to be clinically insignificant (score 0–3), mild (score 4–5), moderate (score 6–8), or severe (score 9 or greater). Gastroscopy, duodenoscopy, and colonoscopy were performed in all dogs except those with panhypoproteinemia. Colonoscopy was not performed in these dogs because a 36-hour fast was considered detrimental in these patients. The dogs were assigned an endoscopy score for duodenum and colon by either 2 of the authors performing the endoscopies (KA and FG). Scores were assigned as follows: normal mucosa 5 0; slightly friable mucosa and increased erythema 5 1; friable mucosa with white speckling on the surface 5 2; very friable mucosa, bleeds easily, with visible ulcers or cobble-stone appearance, difficulty in insufflating the bowel endoscopically 5 3. Finally, mucosal biopsy specimens from stomach, duodenum, and colon were examined histologically and graded according to previously published guidelines.8 Five biopsy specimens from each site were examined histologically. Mild lesions were those with cellular infiltrates but without architectural distortion or mucosal epithelial immaturity. Moderate lesions had cellular infiltrates accompanied by mucosal epithelial immaturity, solitary epithelial necrosis, or both. Severe lesions consisted of cellular infiltrates accompanied by multifocal epithelial necrosis or extensive architectural distortion with epithelial immaturity. All dogs initially were treated with an elimination dietb for 10 days. Dogs that responded to the elimination diet in the 1st 10 days (clinical signs improved or resolved) were assigned to the food-responsive group (FR). The dogs that did not respond in the 1st 10 days of treatment (clinical signs persisted while on the elimination diet) were assigned to the steroid-treatment (ST) group, and were given oral prednisolone (2 mg/kg per day PO) for 10 days followed by a tapering dosage over 10 weeks. Thus, dogs were separated into 2 groups according to their initial response to treatment with elimination diet. Although it is possible that these dogs still had IBD, we assigned them into the FR group according to their prompt response to dietary treatment alone. The FR group
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was re-evaluated 4 weeks after starting treatment with the elimination diet. At this time, the CIBDAI score was re-evaluated and endoscopy was repeated to determine the posttreatment endoscopy score and histopathology grade. The ST group was reexamined a 2nd time including an endoscopy at the end of the 10-week treatment period, which was 2 weeks after complete discontinuation of prednisolone treatment. All dogs were fed the elimination diet exclusively for 14 weeks. Ten dogs in the ST group were clinically classified as having protein-losing enteropathy (PLE group) because of panhypoproteinemia with severe hypoalbuminemia (mean albumin concentration, 11.3 g/L; SD 3.19; range, 10–18 g/L; reference range, 24–35 g/L) and ascites, with or without pleural effusion or peripheral edema. A 2nd prospective treatment trial was performed on all dogs that did not respond to the initial 10-week course of prednisolone (reduction of CIBDAI minimal to absent). These dogs underwent the same clinical and laboratory examinations as described above. All of them were completely weaned from the prednisolone treatment before receiving cyclosporine at 5 mg/kg PO for a total of 10 weeks,c when a 2nd endoscopy and clinical assessment was performed.
Statistical Analysis Normally distributed data are reported as means 6SD. Data that were not normally distributed are reported as medians (ranges) unless otherwise indicated. Outcome was defined as good if the dog was still alive 3 years after finishing treatment; negative outcome was defined as the dog having been euthanized any time during the 3 years of the study because of refractoriness to treatment. A oneway analysis of variance (ANOVA), Kruskal-Wallis test for nonparametric data, and logistic regression models with 1 predictor were used to evaluate differences among the groups of dogs. Cross tabulations were performed using a Fisher’s exact or chi-square test. Correlations were evaluated with the Spearman rank correlation test. Odds ratios (ORs) were determined using logistic regression models with a single predictor. Multivariate logistic regression analysis was attempted, however, sample size was too small in the subgroups to control for influence of more than 1 variable. Potential clinical scoring systems with different combinations of the risk factors identified by univariate logistic regression analysis were evaluated using the area under the curve (AUC) of binomial receiver operator characteristic (ROC) curves. For each scoring system, the optimum cut off was determined, sensitivity and specificity estimated, and AUC was used to compare the efficacy of the scoring systems for predicting negative outcome. A new scoring system was named canine chronic enteropathy clinical activity index (CCECAI), and included the lowest serum albumin concentration measured at any time point during the study (15–19.9 g/L, score of 1; 12–14.9 g/L, score of 2; ,12 g/L, score of 3), subjective scoring of peripheral edema and ascites (scores of 1– 3), and subjective owner assessment of severity of pruritus (scores 1–3) in addition to the composite score previously published as CIBDAI6 (Table 1). The following scoring systems were evaluated for their effectiveness in predicting outcome: CIBDAI as previously described,6 CIBDAI plus serum albumin concentration, CIBDAI plus serum cobalamin concentration, CCECAI, CCECAI plus serum cobalamin concentration, CCECAI plus serum cobalamin concentration and endoscopic score. Statistical significance was set at P , .05. All statistical analyses were performed using a commercially available statistical software system.d
Results Breeds, Age, Sex, and Weight Seventy dogs were included in the prospective treatment trial. Thrity-nine dogs were included in the
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Table 1. Comparison of clinical activity indices (CIBDAI versus CCECAI). Canine inflammatory bowel disease activity index (CIBDAI)6 Attitude/activity 0 1 2 3
normal slightly decreased moderately decreased severely decreased
Canine Chronic Enteropathy activity index (CCECAI) Attitude/activity 0 1 2 3
normal slightly decreased moderately decreased severely decreased
Appetite 0 normal 1 slightly decreased 2 moderately decreased 3 severely decreased
Appetite 0 normal 1 slightly decreased 2 moderately decreased 3 severely decreased
Vomiting
Vomiting
0 1 2 3
normal mild (13 per week) moderate (2–33/wk) severe (.33/wk)
Stool consistency 0 1 2 3
normal slightly soft feces very soft feces watery diarrhea
Stool frequency 0 normal 1 slightly increased (2–33/d) or fecal blood, mucus or both 2 moderately increased (4–53/d) 3 severely increased (.53/d) Weight loss 0 1 2 3
none mild (,5%) moderate (5–10%) severe (.10%)
0 1 2 3
normal mild (13/wk) moderate (2–33/wk) severe (.33/wk)
Stool consistency 0 1 2 3
normal slightly soft feces very soft feces watery diarrhea
Stool frequency 0 normal 1 slightly increased (2–33/d) or fecal blood, mucus, or both 2 moderately increased (4–53/d) 3 severely increased (.53/d) Weight loss 0 1 2 3
none mild (,5%) moderate (5–10%) severe (.10%)
Albumin levels 0 1 2 3
albumin albumin albumin albumin
.20g/L 15–19.9 g/L 12–14.9 g/L ,12 g/L
Ascites and peripheral edema 0 none 1 mild ascites or peripheral edema 2 moderate amount of ascites/ peripheral edema 3 severe ascites/pleural effusion and peripheral edema Pruritus 0 no pruritus 1 occasional episodes of itching 2 regular episodes of itching, but stops when dog is asleep 3 dog regularly wakes up because of itching
FR group and 21 required prednisolone in addition to the elimination diet (ST group). Ten dogs were clinically classified as having protein-losing enteropathy (PLE group) because of panhypoproteinemia with severe hypoalbuminemia (mean serum albumin concentration, 11.3 g/L SD 3.19; range, 10–18 g/L; reference range, 24– 35 g/L) and ascites, with or without pleural effusion or peripheral edema. Breeds included in the study and groups assigned to the study dogs were as follows: FR group (n 5 39): Golden Retriever (6), Mixed Breed (6), Labrador Retriever (5), German Shepherd (3), Bernese Mountain Dog (2), Cairn Terrier (2), Malinois (2), Alaskan Malamute (1), Border Collie (1), Border Terrier (1), Chihuahua (1), Dachshund (1), English Setter (1), Great Dane (1), Greyhound (1), Jack Russell Terrier (1), Leonberger (1), Shi Tzu (1), West Highland White Terrier (1), and Whippet (1); ST group (n 5 21): Mixed Breed (6), Boxer (2), German Shepherd Dog (2), Yorkshire Terrier (2), Coton de Tulear (1), Dachshund (1), Dalmation (1), Mastiff (1), Papillon (1), Rottweiler (1), Shar Pei (1), Toy Poodle (1), and West Highland White Terrier (1); and PLE group (n 5 10): Mixed breed (4), Yorkshire Terrier (4), Dachshund (1), and West Highland White Terrier (1). There were 34 females in the study population, of which 22 were spayed, and 36 males, 15 of which were neutered. There was no statistically significant difference in the sex distribution between the 2 groups. Mean age of the total study population was 5.3 6 2.9 years (range, 6 months to 13 years). The mean age of the FR group was significantly lower than that of the ST group and PLE group (FR group: mean 3.53 6 2.36 years, range 0.6–7.6, median 3.4 years; ST group: mean 6.52 6 2.94 years, range 2.1–13, median 4.8 years; PLE group: mean 7.33 6 3.93 years, range 2.5–13, median 7.6 years; P , .001).
Long-term Outcomes The odds ratios (ORs) for negative outcome for each of the clinicopathologic variables are presented in Table 1. In the FR group, all dogs but 1 were still alive 3 years after ending the study. All 39 dogs were switched back to their original diet after 14 weeks of elimination diet trial. In 31 of 39 dogs, the original signs did not recur and the dogs subsequently did not develop signs of their disease for up to 3 years of follow up. In the remaining 8 dogs, switching back to the original diet lead to a recurrence of disease, and therefore, these dogs were suspected of having food allergy or food intolerance. These 8 dogs then were challenged orally with 4 different single proteins (beef, lamb, chicken, and milk). Only 2 dogs showed a clinical reaction, with acute vomiting and hematochezia 1 day after eating the provocative diets. In 1 of these 2 dogs, we were unable to find a diet that did not elicit any signs for the next 2 years. This dog also was on trial treatment with corticosteroids and cyclosporine, but responded only minimally. This dog eventually was euthanized because of recurring signs.
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Endoscopy Score There was no difference in endoscopy score among the FR, ST, and PLE groups. The same was true within the same group before and after treatment (median scores in the FR and ST groups 1.3, range 0–3, median scores after treatment in the FR group 1.2, range 0–3, and in the ST group 1.3, range 0–3; P 5 .27; median scores in the PLE group before treatment: 1.8, range 0– 3, median score after treatment 1.9, range 0–3, P 5 .26). No correlation was found between endoscopy scores and CIBDAI or histologic scores (P 5 .12). However, an endoscopy score of 3 in the duodenum (indicating severe inflammation) was significantly associated with negative outcome (OR 10.5, CI 95%: 1.7–66.1, P 5 .01).
Histologic Scoring
Fig 1. Numbers of dogs in each group presenting with signs of predominantly small-intestinal, large-intestinal, or mixed clinical signs. FR, food-responsive group; ST, steroid-treatment group; PLE, protein-losing enteropathy group.
The other 7 dogs showed only minor clinical signs on the provocative diet. These dogs subsequently were fed their specific elimination diets and remained clinically normal. Ten of 21 dogs in the ST group responded to the initial treatment with immunosuppressive doses of steroids and did not show any relapses for another 3 years after the study was completed. Of the other 11 patients, 3 were euthanized after the corticosteroid trial. The remaining 8 dogs were subsequently treated with cyclosporine, which rescued 2 of 8 dogs from euthanasia. In the PLE group, none of the dogs responded to the initial corticosteroid treatment trial and subsequently went on to cyclosporine treatment. This protocol rescued 7 of 10 PLE dogs from euthanasia. Dogs in the ST group and PLE group had a significantly higher chance of becoming refractory to treatment and being euthanized within 3 years after finishing the treatment trial than did dogs in the FR group (ST group: OR 28.5 [CI 95%: 3.3; 248.5, P , .01]; PLE group: OR 16.3 [CI 95%: 1.5; 180, P , .05]).
Predominance of Clinical Signs: Small versus Large Intestinal Disease The initial presenting complaint predominantly involved the small intestine in 30 dogs, predominantly the large intestine in 26 dogs (86% of dogs in the FR group), and both the small and large bowel in 14 dogs. When comparing the groups of FR and ST, large intestinal signs were significantly more frequently seen in the FR than in the ST and PLE groups (P , .001) (Fig 1). Signs of predominantly small intestinal disease were significantly correlated with a higher CIBDAI score (P , .01).
Histologically, all dogs showed some degree of infiltration with lymphocytes, plasma cells, eosinophils, or some combination of these. In 4 dogs, mild lymphangiectasia was evident histologically, but the accompanying inflammatory infiltrate was judged by the pathologist (AG) to be severe enough to cause secondary lymphangiectasia. There was no statistically significant difference among the 3 groups for histologic scoring (histologic scoring in the FR group before treatment: median 1.8, range 0–3; after treatment: median 1.9, range 0–3, P 5 .11; histologic scoring in the ST group before treatment: median 1.4, range 0–3; after treatment: median 2.3, range 0–3; P 5 .09; histologic scoring in the PLE group before treatment: median 1.7, range 0–3, after treatment: median 2.1, range 0–3; P 5 .12). In addition, histologic scores were not correlated with CIBDAI, endoscopy scoring, or outcome.
Serum Albumin Concentrations Fifteen of 70 dogs initially presented with a hypoalbuminemia of ,20 g/L. Of these 15 dogs, 10 were panhypoproteinemic with severe hypoalbuminemia (PLE group). These dogs also showed clinical evidence of PLE, such as ascites (15 of 15), peripheral edema (1 of 15), and thoracic effusion (1 of 15). Eight dogs with hypoalbuminemia eventually were euthanized because of refractoriness to treatment including 3 dogs with PLE. Serum albumin concentration was not correlated with CIBDAI, endoscopic or histologic scoring (CIBDAI: P 5 .12; endoscopic scoring: P 5 .23, histologic scoring: P 5 .09). In the univariate regression analysis, the lowest serum albumin concentration measured at any time point during the study was significantly associated with disease outcome when a cut off of ,20 g/L was chosen (OR 11.4, CI 95% 2.9–44.9, P , .01).
Serum Cobalamin Concentrations Thirteen of 70 dogs had initial hypocobalaminemia with concentrations ,200 ng/L (6 in the ST group, 6 in the PLE group, and 1 in the FR group). Mean cobalamin concentration in these 13 dogs was 129.3 ng/L, SD 32.4 (range, 100–224 ng/L; reference
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treatment; P , .01; PLE group median 10.8 before [range, 3–16] versus 5.1 (range 0–16) after treatment, P , .01). Details on the CIBDAI score are presented in Figure 2. There was no significant association between the CIBDAI and the histologic or endoscopic scores. However, outcome was significantly associated with CIBDAI (OR 1.48, CI 95% 1.06–2.06, P 5 .02).
Evaluation of Scoring Systems for CE
Fig 2. Canine inflammatory bowel disease activity index (CIBDAI) scores for dogs in the FR, ST, and PLE group. FR, foodresponsive group; ST, steroid-treatment group; PLE, protein-losing enteropathy group.
range, 249–733 ng/L). Dogs with low serum cobalamin concentrations were treated with weekly cobalamin injections (dogs #15 kg body weight: 500 mg per injection; dogs .15 kg body weight: 1000 mg per injection), which successfully corrected the cobalamin concentrations into the normal range within 10 weeks in all dogs. Seven of 13 dogs with initial hypocobalaminemia were subsequently euthanized because of refractoriness to treatment. Dogs with initial serum cobalamin concentration below the cut off value of 200 ng/L had a highly significant higher chance for a negative outcome (OR 9.5, CI 95% 2.5–39.4, P , .01) in the univariate analysis. In addition, there was a highly significant association between a low serum albumin concentration and a low serum cobalamin concentration (chi square 29.21, P , .001).
Serum CRP Concentrations In 33 of 70 dogs, serum CRP concentration was measured before and after treatment. Based on established reference ranges, serum CRP was increased in 7 of these 33 dogs before treatment and in none of the dogs after treatment (0.55 6 1.67 mg/L; reference range, 0–7.6 mg/le). Serum CRP concentration did not correlate with CIBDAI, endoscopic, or histologic scoring, or outcome.
Severity of Disease and Clinical Disease Activity Index The CIBDAI was significantly lower in the FR group than in the ST group and the PLE group before starting treatment (P , .01). Clinical signs improved during therapy in all groups, but the magnitude of improvement was significantly greater in the FR group than in the ST or the PLE group (FR group: median initial CIBDAI 6.3 [range: 2–12] versus 1.2 [range, 0–7] after treatment; P , .01; ST group: median CIBDAI 8.3 [range, 2–15] before versus 5.5 [range, 0–16] after
With univariate screening, potential risk factors for negative outcome were identified (Table 2). Some clinical variables seemed to be important predictors of outcome in the FR and PLE group. However, these factors were not identified to be statistically significant in the regression analysis because of insufficient numbers in the subgroups. In the FR group, pruritus was the only factor that impacted on a negative outcome for the dog that had to be euthanized in this group. In the PLE group, serum albumin concentration was not a very strong negative predictive factor, but the clinical signs associated with disease, such as ascites and peripheral edema, impacted more on the outcome in this group. These 2 clinical variables were added to the new scoring system to make it applicable to all dogs with CE. Six different scoring systems based on the previously published CIBDAI6 were defined and evaluated for their usefulness in predicting negative outcome, as described in the Materials and Methods section. All scoring systems based on the newly defined CCECAI performed at similar level with an AUC above 0.93. For the CCECAI a cutoff value of 12 was shown to be the best predictor for negative outcome, with a sensitivity of 0.91 and a specificity of 0.83 (Fig 3; Table 3). Similar to the CIBDAI, 4 categories of severity were defined for the CCECAI: insignificant disease, 0–3; mild disease, 4– 5; moderate disease, 6–8; severe disease, 9–11; very severe disease, $12. Details of numbers of dogs grouped in the different categories of severity are shown in Figures 2 and 4.
Discussion In this prospective study of 70 dogs with CE, standard tests and previously proposed markers of disease were evaluated for their usefulness in predicting response to therapy (either food-responsive disease or steroid-responsive disease) as well as for predicting outcome (ie, euthanasia due to refractoriness to treatment). The number of cases with intractable disease was 13 of 70 dogs (18%), which is comparable to 13 of 80 dogs (16%) as recently reported in a retrospective study.5 The mean age of our study population was 5.3 years, which concurs with previously reported age ranges in dogs with chronic intestinal disease.1,5 The mean age of the dogs with food-responsive disease was significantly lower than that of dogs that had to be treated with steroids in addition to the elimination diet. Diet-responsive CE in dogs occurs predominantly in younger dogs.3 Food allergy associated with dermatologic signs also is
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Table 2. Results of the univariate logistic regression analysis of each clinicopathologic variable with outcome, which was defined as euthanasia because of refractoriness to treatment at any time point during the study. ST and FR Group Risk Factors
ST, FR, and PLE Group
OR
CI 95%
P
OR
CI 95%
P
5.6 3.7 1
0.9–33.2 0.5–25.2 1
.06 .18 1
5.7 3.7 1
1.1–29.8 0.5–25.2 1
.04 .18 1
28.05
3.3–248.5
,.01
28.5 16.3 1
3.2–248.5 1.5–180 1
,.01 .02 1
Predominant clinical presentation of disease Small intestinal Small and large intestinal Large intestinal Clinical group IBD PLE FRD
1
Albumin ,2g/L CRP . 0 Cobalamin ,200ng/L Endoscopy Duodenum Score 0 Score 1 Score 2 Score 3
1
1
49 0.48 10.4
4.7–506.6 0.1–3 1.9–58.4
,.01 .43 ,.01
11.4 11.4 9.9
2.9–44.9 0.5–27.1 2.5–39.4
,.01 .12 ,.01
1 2.8 0.9 15.8
1 0.5–17.3 0.1–10.7 1.6–157.6
1 .27 .91 .02
1 2.8 0.7 10.5
1 0.5–17.3 0.1–8.4 1.7–66.1
1 .27 .8 .01
1 0.4 0.6 5.2
1 0.1–3.5 0.1–6 0.6–49
1 .37 .65 .14
1 0.4 0.6 5.2
1 0.1–3.5 0.1–6 0.6–49
1 .37 .65 .14
1 2.8 6.5
1 0.3–24.7 0.5–91.9
1 .36 .17
1 2.9 9.8
1 0.3–25.3 0.8–121.8
1 .33 .08
1 1.1 1.6
1 0.2–6.7 0.1–16.9
1 .89 .72
1 1.l 1.6
1 0.2–6.7 0.1–16.9
1 .89 .72
1.5
1.1–2.1
.02
1.4
1.1–1.8
,.01
Endoscopy Colon Score Score Score Score
0 1 2 3
Histology Duodenum Score 0 + 1 Score 2 Score 3 Histology Colon Score 1 Score 2 Score 3 CIBDAI
OR, odds ratio; CI, confidence interval; CRP, C-reactive protein; CIBDAI, canine inflammatory bowel disease activity index6; ST group, steroid-treatment group; FR group, food-responsive disease group; PLE, protein-losing enteropathy group.
observed at a relatively young age.9 This study confirms the results obtained in a smaller group of dogs from the same population.7 Breed distribution in the 3 groups indicated increased numbers of small breeds such as Yorkshire Terriers, West Highland White Terriers, and Dachshunds in the ST and PLE groups. Yorkshire Terriers previously have been reported to be at risk for developing PLE from lymphangiectasia.10 Dogs with food-responsive disease were more likely to present with complaints related to the large intestine than were those in the ST group. The observation that large-bowel clinical signs were more common in dogs in the FR group than in those of the ST and PLE groups is an original finding. Moreover, the severity of clinical signs was significantly lower in food-responsive dogs. These observations suggest that younger dogs with less severe disease, and a predominance of large intestinal signs are more likely to respond to elimination diet alone. Our data also imply that a dog responding relatively quickly to treatment with elimination diet alone (ie, within 1– 2 weeks) will most likely have a good long-term
prognosis. Most dogs in the FR group could be switched back to their original diet without recurrence of clinical signs for 3 years after initial diagnosis. To the contrary, middle-aged to older dogs with more severe disease and predominantly small-intestinal diarrhea are more likely to require steroid treatment to improve. In addition, they also are more likely to be euthanized because of intractable disease. The presence of severe mucosal lesions in the duodenum was significantly associated with negative outcome in the univariate analysis. No such association could be identified for endoscopic score in the colon. Hence, endoscopic identification of severe mucosal lesions in the duodenum of a dog with CE may warrant initiation of more aggressive treatment early in the course of disease. Surprisingly, in the 70 dogs of the present study, histologic score was not associated with outcome. This is consistent with observations made in a recent retrospective study, in which severity of histologic changes was not associated with outcome.5 It also has recently been
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Fig 3. Receiver operator characteristic (ROC) curves comparing the ability to predict negative outcome of the 2 scoring systems, canine inflammatory bowel disease activity index (CIBDAI6) and the new proposed canine enteropathy clinical activity index (CCECAI). Odds ratios of different scoring systems (5 chance for negative outcome when score goes up 1 point): CIBDAI: OR 1.4, P , .01, CI 95%: 1.1–1.8, CCECAI: OR 1.8, P , .01, CI 95%: 1.3–2.4. Cut off for CIBDAI: 9; cut off for CCECAI: 12. (A) ROC curves for CIBDAI (binomial and empirical values). (B) ROC curves for CCECAI curves (binomial and empirical values).
demonstrated that the histopathologic evaluation of canine intestinal biopsies strongly depends on the quality of biopsy specimen and the individual subjective assessment of the pathologist.11 This is especially important in the case of endoscopic biopsies, for which the quality of the specimens can be very variable. In the present study, a single pathologist performed all assessments according to criteria proposed in a previous study,1 and was blinded as to the identity of the samples. Taken together, these data question the value of
histopathology in the assessment of dogs with CE, other than being useful to exclude certain other intestinal diseases such as neoplasia or histiocytic ulcerative colitis. Clearly, other variables seem to be more helpful for the clinician, such as clinical grading of disease severity and assessment of therapeutic response in dogs with CE. Hypoalbuminemia previously has been reported to be associated with refractoriness to treatment.5 Serum albumin concentration obviously is related to the hydration status of the animal and may change over the course of treatment, especially during and after fluid therapy. We therefore selected the lowest serum albumin concentration measured at any time during the study for each individual dog for statistical analysis. Hypoalbuminemia with concentrations ,20 g/L was found to be strongly associated with negative outcome in the univariate analysis. This suggests that it may be helpful to include this variable in the overall clinical assessment of dogs with CE. Low serum cobalamin concentration is a variable that has been associated with refractoriness to treatment in cats with CE.12,13 In dogs with CE, hypocobalaminemia has been predominantly described in antibiotic-responsive diarrhea or in dogs with exocrine pancreatic insufficiency,14–16 in which classically a low serum cobalamin concentration is seen in combination with hyperfolatemia. In our study, a cobalamin concentration ,200 ng/L was significantly associated with negative outcome, although all hypocobalaminemic dogs received vitamin B12 supplementation for 6 weeks. These data suggest that low serum cobalamin concentration at the time of diagnosis may predict refractoriness to treatment, as has been reported in cats. Cobalamin and albumin however were strongly correlated, and both parameters should be assessed together in each dog. In a recent study, CRP was described as a marker of disease severity in dogs with CE,6 because serum CRP concentrations were indirectly correlated with CIBDAI and histologic scoring. This finding is in disagreement with the findings of the present study, in which CRP was only high in 7 of 33 dogs. The 33 dogs that had CRP measured had moderate severity of disease and represented a wide range of clinical severity of disease (CIBDAI in dogs in which CRP was measured: median 5.5 mg/L, range 1–15 mg/L). High CRP concentrations may have been missed in several animals because CRP
Table 3. Receiver operator characteristic (ROC) curve analysis for different clinical scoring systems. Test CIBDAI CIBDAI + albumin CIBDAI + cobalamin CCECAI CCECAI + cobalamin CCECAI + cobalamin + endoscopy score duodenum
AUC
Standard error AUC
CI 95%
Best cut-off
Sensitivity (%)
Specificity (%)
0.75 0.76 0.80 0.93 0.94
0.069 0.073 0.068 0.029 0.029
0.58–0.86 0.57–0.87 0.61–0.90 0.84–0.97 0.84–0.97
8 9 9 12 13
74 67 69 91 86
63 71 72 82 87
0.94
0.029
0.84–0.97
14
87
86
AUC, area under the curve; CI, confidence interval; CCECAI, canine chronic enteropathy clinical activity index; CIBDAI, Canine inflammatory bowel disease activity index.6
Risk Factors in Canine IBD
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clinical signs, and predominantly have small-intestinal diarrhea. Based on the results of this study, we devised a new clinical scoring system that may be used for all dogs with CE. The CCECAI scoring index includes hypoalbuminemia (serum concentrations ,20 g/L), assessment of ascites, peripheral edema and pruritus in addition to the CIBDAI scores.
Footnotes a
Fig 4. Canine chronic enteropathy activity index (CCECAI) scores for dogs in the FR, ST, and PLE group. FR, foodresponsive group; ST, steroid-treatment group; PLE, protein-losing enteropathy group.
was measured in less than half of the dogs described. Additional studies elucidating the role of CRP as a marker in dogs with CE are warranted. CIBDAI previously has been described in a large prospective study with short-term follow up, but no information about long-term outcome was available.6 In the present study, we showed that severity of disease as assessed by clinical scoring is also associated with longterm disease outcome. However, adding low serum albumin concentrations, and assessment of ascites and pruritus to the CIBDAI to define the new clinical scoring system CCECAI was much more powerful to accurately predict negative outcome. Including low cobalamin concentrations and results of more invasive tests such as endoscopy to the scoring system did not add any additional benefit regarding predictive ability of the scoring system. Because serum albumin concentration is more widely available in routine small animal practice, we chose to use this variable in the CCECAI. Cobalamin is equally powerful as a predictive factor but may not be as readily available for practitioners. Jergens et al6 excluded dogs with food-responsive disease as well as PLE dogs from their trial, whereas in our study the prospective nature of a step-wise treatment protocol made it possible to include food-responsive dogs, dogs that needed steroid treatment, as well as PLE dogs. Therefore, this new score may be valuable for all dogs with chronic intestinal disease after exclusion of endoparasites and enteropathogens, and could be used widely under such circumstances. In conclusion, the results of this study suggest that several clinical as well as clinicopathologic variables are useful to predict response to treatment and outcome in dogs with CE. Dogs with food-responsive disease generally are younger, are presented with less severe clinical signs and predominantly have large-intestinal diarrhea. Dogs that need to be treated with steroids are middle-aged to older, are presented with more severe
Tridelta PHASE RANGE Canine C-Reactive Protein Assay, Tridelta, Wicklow, Ireland b Purina L/A salmon and rice, Nestle´ Purina, Udine, Italy c Atopica, Novartis Animal Health, Basel, Switzerland d NCSS Statistical Software version 2005, Kaysville, Utah e Berghoff N et al. Canine CRP: Determination of a reference range and its stability in serum samples. ACVIM Forum, 2006 Louisville, KY, (abstract)
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