Abstract
Case Description—A 1.5-year-old mixed-breed dog was examined because of a 1-month history of anorexia, vomiting, diarrhea, and weight loss.
Clinical Findings—The dog was very thin on physical examination (body condition score, 3/9). Results of all diagnostic tests were within reference limits except intestinal thickening and lymphadenopathy were identified on abdominal ultrasound examination. During exploratory laparotomy, thickening at the ileocecal-colic junction and within the transverse colon and mesenteric lymphadenopathy were identified, and the ileocecal-colic junction was resected. Histopathologic evaluation of the ileocecal-colic junction and full-thickness biopsy specimens from other sites as well as results of a serum ELISA were diagnostic for gastrointestinal Pythium insidiosum infection.
Treatment and Outcome—Pythiosis was initially treated medically with administration of itraconazole and terbinafine by mouth, but the colonic lesion was progressive with this regimen. Two months after diagnosis, a subtotal colectomy was performed; marginal excision (0.6 cm) was obtained at the aboral margin. The dog was treated with 3 doses of a pythiosis vaccine beginning approximately 2 weeks after surgery and was continued on itraconazole and terbinafine for 5 months. Parenteral and enteral nutrition as well as considerable general supportive care were required postoperatively. Six months after treatment, the dog had a normal serum ELISA titer. Two years after treatment, the dog had returned to preoperative weight and was clinically normal.
Clinical Relevance—This patient had an unusually positive therapeutic response to chronic, extensive, marginally excised gastrointestinal pythiosis.
A 1.5-year-old neutered male mixed-breed dog with a 1-month history of vomiting, diarrhea, anorexia, and weight loss was evaluated. It was estimated by the owners that the dog lost approximately 10% of its weight during the month prior to admission. The diarrhea was characterized by small amounts of frank blood. On initial physical examination, the dog was bright and alert. Temperature, pulse, and respiratory rate were within normal ranges. The dog was thin (body condition, 3/9; weight, 23.6 kg [51.9 lb]), but otherwise, results from the physical examination, including a rectal examination, were normal.
A CBC and serum biochemistry profile were performed, and the dog had no notable abnormalities. The urinalysis results were normal with the exception of a low specific gravity (1.013). A heartworm antigen test and fecal flotation test were performed, and results of both tests were negative. Thoracic and abdominal radiographs were also normal. Abdominal ultrasonography was performed, and a focal area of intestinal thickening was observed; however, the exact location of the thickening within the bowel was not able to be identified. Mesenteric lymph node enlargement was noted in multiple lymph nodes. The largest node was seen near the thickened intestinal segment. To obtain full-thickness biopsies of the thickened intestines and the enlarged lymph nodes, an exploratory laparotomy was performed.
The day following admission, the patient was anesthetized, and a routine exploratory laparotomy via ventral midline approach was performed. There were 2 areas of the colon that appeared grossly abnormal. One was at the ileocecal-colic junction, and the other was approximately 6 cm aboral to the ileocecal-colic junction in the distal transverse colon. The ileocecal-colic junction lesion was firm and thickened circumferentially with adhered mesentery and enlargement of associated lymph nodes. The lesion on the transverse colon was a firm plaque approximately 1 cm in diameter on the antimesenteric border. Other than the abnormalities of the intestine and lymph nodes, there were no abnormalities identified on exploration of the abdomen. The thickened bowel wall was aspirated with a 22-gauge needle, and cytologic examination demonstrated moderate to severe pyogranulomatous inflammation. Tissue imprint cytologic examination was performed on the enlarged lymph nodes, which were cytologically consistent with a reactive inflammation. Cytologic samples were also obtained from several other portions of the small and large intestine via fine-needle aspiration of the intestinal wall for comparison and were determined to be normal on cytologic examination.
To obtain a definitive diagnosis, the ileocecal-colic junction was removed in toto. An end-to-end ileocolonic anastomosis was performed with 3-0 polydioxanonea in a simple interrupted pattern. Because the differential diagnoses included neoplasia and infection, full-thickness biopsies were also obtained from the antimesenteric surface of the more distal abnormal colon as well as from the stomach, ileum, and jejunum. The intestinal biopsy sites were closed with 3-0 polydioxanonea in a simple interrupted pattern. Several mesenteric lymph nodes were biopsied via a wedge biopsy technique, and the capsule and defect in the lymph node were closed with 3-0 polydioxanonea in a horizontal mattress pattern. Abdominal closure was performed routinely in 3 layers with 0 polydioxanonea in the linea alba, 3-0 polydioxanonea in the subcutaneous tissue, and stainless steel staplesb in the skin. An esophagostomy tube was inserted prior to anesthetic recovery.
Results of histologic examination of biopsy samples of the stomach and jejunum were within normal limits, and the lymph nodes were hyperplastic. The sections of ileum, cecum, and colon were characterized by multifocal to coalescing submucosal pyogranulomas, many with prominent multinucleated foreign body giant cells that sometimes extended into the muscular layers (Figure 1). The overlying mucosa was ulcerated in the more severely affected areas. In 1 section, a large artery was incorporated into a granuloma and contained necrotic debris and a fibrin thrombus. Sections stained for fungi with Gomori methenamine silver revealed numerous fungal hyphae at the center of the granulomas. The granulomas were surrounded by hemorrhage and degenerate and nondegenerate eosinophils. The fungal hyphae contained globose swellings and thus varied in size, ranging from 5 to 14 μm in diameter; they also had nonparallel walls, rare septa, and infrequent branching. The histologic characteristics of the fungal elements were typical of Phythium insidiosum. This diagnosis was confirmed with a positive result of a serum ELISA titer for anti—P insidiosum IgG antibodies.1 The titer was 88% (percent positivity in relation to a strong positive control as determined at the Louisiana State University Pythium Laboratory, Baton Rouge, La).
Photomicrographs of specimens obtained during an exploratory laparotomy of a 1.5-year-old mixed-breed dog with a subsequent diagnosis of gastrointestinal pythosis. A—A full-thickness section of small intestine is characterized by ulceration of the mucosa with accumulation of necrotic debris and multifocal deep coalescing granulomas. H&E stain; bar = 2 mm. B—Small intestinal granuloma. There are numerous macrophages and multinucleated foreign body giant cells and smaller aggregates of neutrophils. H&E stain; bar = 200 μm. C—Fungal hyphae consistent with Pythium spp in the small intestinal lesions. Gomori methenamine silver stain; bar = 100 μm.
Citation: Journal of the American Veterinary Medical Association 241, 3; 10.2460/javma.241.3.358
Before the results of the histologic examination were received, the dog recovered from anesthesia and surgery without complications. Postoperatively, the patient received IV isotonic fluid therapyc at maintenance rate supplemented with 16 mEq/L of potassium chloride, hydromorphone (0.05 mg/kg [0.02 mg/lb], IV, q 4 to 6 h), and enrofloxacin (10 mg/kg, [4.55 mg/lb], IV, once daily). The dog was discharged from the hospital 5 days after surgery and was treated with enrofloxacin (6.8 mg/kg [3.09 mg/lb], PO, once daily). During postoperative hospitalization, the dog was eating normally and consuming adequate calories, so the esophageal feeding tube was not used.
After the biopsy results were received, options were discussed with the owner, including additional surgery to remove as much of the affected tissue as possible or medical management. Because of concerns about constant chronic diarrhea following subtotal colectomy, the potential inability to get wide surgical margins, and the poor overall prognosis, the owners opted for medical treatment alone. The dog began treatment with itraconazole (10 mg/kg, once daily) and terbinafine (12 mg/kg [5.5 mg/lb], once daily).2 These medications were administered through the esophagostomy tube along with tramadol (2 mg/kg [0.9 mg/lb], q 8 h) for pain. The owners were advised that the esophagostomy tube could be used for nutritional support should the dog stop consuming an adequate amount of food.
Approximately 1 month following surgery, the dog was seen for a follow-up examination. Over the month, the anorexia had returned, and the owners had begun using the esophagostomy tube to supplement the dog's voluntary intake. The rectal temperature was elevated (39.8°C [103.7°F]). The tissue around the esophagostomy tube site was hyperemic and edematous with purulent discharge. The esophagostomy tube was also no longer patent. The esophagostomy tube was removed and replaced with a PEG tube. At this time, the dog had gained approximately 1 kg (2.2 lb) since surgery. Anorexia persisted, and soft stools with occasional blood were reported. Four days after the PEG tube was placed, the dog removed the tube. The stoma was identified, and another tube was placed. The second PEG tube was removed by the dog approximately 3 weeks later (about 2 months following the initial diagnosis).
After the second patient PEG tube removal, the stoma could not be definitively identified and salvaged, and the decision was made to replace the gastrostomy tube surgically because nutritional support was mandatory. At that time, the dog's quality of life was deteriorating. An approximately 4-kg (8.8-lb) weight loss was noted since first examination, and the dog had substantial signs of pain during defecation. At that time, the PCV was 43% and the total protein was 8.0 mg/dL. Venous blood gas parameters and electrolyte, glucose, BUN, and creatinine concentrations were all within reference limits. A firm, approximately 10 × 6-cm, caudal abdominal mass was detected on physical examination and appeared painful on palpation. Colonic involvement at the site of the previous plaque lesion was suspected. The decision was made to attempt resection of the mass to palliate the dog's pain and improve the quality of life.
At repeated laparotomy, the entirety of the remaining colon was effaced by a large, firm, columnar mass approximately 6 cm in diameter. The mass extended orally past the site of the previous resection and anastomosis into the distal jejunum. Aborally, the lesion extended to the level of the pubis. There were multiple areas of mesenteric adherence, multiple enlarged lymph nodes, and involvement with the caudal aspect of the mesenteric root and the caudal mesenteric artery. To accomplish a complete resection as well as ensure a tension-free anastomosis, approximately 40 cm of small intestine as well as 11 cm of colon was removed. This allowed for resection of approximately 4 cm of normal intestine on the oral aspect of the lesion and less than 1 cm of normal colon on the distal margin. Enlarged lymph nodes were removed with the intestinal segment; however, other enlarged lymph nodes in the cranial abdomen were not removed. The midjejunum was anastomosed to the colon immediately aboral to the pubis by use of 3-0 polydioxanonea in a simple interrupted pattern. The luminal disparity of the jejunum and colon was mitigated by an antimesenteric incision in the jejunal segment. A gastrostomy tube was placed prior to abdominal closure, which was routine.
As determined on subsequent histologic examination, the section of resected colon had full-thickness granulomas extending from the mucosa to the serosa. Similar to the previous samples, numerous hyphae could be seen at the center of the granulomas. Other histopathologic findings were similar to those for the original biopsy samples. Hemorrhage and degenerate and non-degenerate eosinophils were observed surrounding the granulomas. Hyphae were observed invading arterioles and were 0.6 cm from the aboral colonic surgical margin. Focal necrotizing arteritis was observed. No hyphae were observed in the lymph nodes.
Following surgery, the dog required considerable supportive care. Constant fetid diarrhea was observed. During the first 7 days following surgery, frequent vomiting and regurgitation occurred despite no administration of treatment orally or through the gastrostomy tube. To treat a presumed ileus, prokinetic drugs were administered including lidocaine (40 mg/kg/min [18.2 mg/lb/min], IV), ranitidine (0.5 mg/kg [0.23 mg/lb], IV), and metoclopramide (2 mg/kg/d, IV). The dog was also maintained on itraconazole and terbinafine via the gastrostomy tube, in addition to buprenorphine (0.01 mg/kg [0.005 mg/lb], IV). Vitamin B12 was administered (400 μg, SC) on a weekly basis.
Partial parenteral nutrition was implemented beginning 24 hours after the second surgery because the hope was that the dog would be able to eat soon following surgery. When the dog continued to be inappetent and unable to tolerate enteral feeding, partial parenteral nutrition was switched to total parenteral nutrition 72 hours after surgery because partial parenteral nutrition was inadequate for nutritional maintenance. The dog remained on total parenteral nutrition for 8 days. Enteral feeding was initiated with 10 ml of water every 4 to 6 hours beginning 5 days after surgery. This was slowly advanced to low-fat chicken broth in small (10 to 20 mL) quantities every 4 hours. After 24 hours of feeding broth, 1 tablespoon of white rice was added to 60 mL of broth and infused in 15-mL aliquots every 4 hours. Gradually, over several days, the broth-to-rice concentration was increased to a 1:1 ratio and fed in increasingly greater quantities. The broth and rice mixture was offered orally approximately 9 days after surgery, and at this point, the dog's appetite was good. Twelve days after surgery, low-fat (2%) cottage cheese was added to the mixture and fed orally as well as through the gastrostomy tube. The volume of this mixture was gradually increased on the basis of the dog's tolerance. During this period of gradual refeeding, electrolyte, phosphorus, and triglyceride concentrations were evaluated daily.
Thirteen days after surgery, the dog received a pythiosis vaccine.c The vaccine was given to maximize therapeutic efforts. No vaccine reaction occurred at the site of injection. The dog was discharged 16 days after surgery and received a second and third dose of the vaccine at 7 and 21 days, respectively, following the first dose. The dog did well at home on a nutritionally balanced cottage cheese, rice, and low-fat–chicken broth diet at 1.25 × resting energy requirement and was introduced to a low-fat commercial dietd 5 weeks after discharge. Body weight gradually increased, as did the dog's ability to hold feces for longer periods of time (1 to 2 hours). Feces remained a liquid consistency. Monthly vitamin B12 injections were administered (400 μg, SC).
Two weeks after discharge, an abdominal ultrasound examination was performed. The area of the anastomosis appeared as expected. Multiple mesenteric lymph nodes were still enlarged. One perisplenic lymph node had peripheral hypoechogenicity and a mixed peripheral-hilar vascular pattern, suggesting that it might be an extension of the pythiosis. On subsequent ultrasound examinations, all lymph nodes reduced in size and became more normal in echogenicity. Two months after surgery, the pythiosis ELISA was repeated and was reduced to 22%.
Approximately 6 months after surgery, a follow-up examination at the referral hospital was performed. The dog was eating a commercial low-fat diete and acting normally at home. The feces remained very liquid in consistency, and although the dog was continent, it could only store feces for about 3 hours. The dog's weight was equivalent to its weight on the initial evaluation 7 months earlier, just prior to the initial diagnosis. Results of a physical examination were normal, and on abdominal ultrasound evaluation, the abdominal lymph nodes were of normal echogenicity. A serum ELISA was repeated and was within reference limits (10%). Approximately 24 months following surgery, the owner reported that the dog continued to do well, was continent, and weighed approximately 25 kg (55 lb).
Discussion
Pythiosis is a condition caused by P insidiosum, an aquatic oomycete of the kingdom Stramenopila. This organism more closely resembles algae rather than a fungus because the cell wall lacks chitin and contains cellulose and β-glucan.2 In dogs and cats, pythiosis can be associated with dermal or gastrointestinal lesions. Gastrointestinal pythiosis is characterized by severe transmural, segmental thickening of the gastrointestinal tract, most commonly involving the gastric outflow or the ileocecal-colic junction.2–5 Treatment of gastrointestinal pythiosis is frustrating, and the prognosis is poor to grave. It is best treated with wide (3- to 4-cm) surgical excision.2–5 The combination of itraconazole and terbinafine treatment has been reported to have some efficacy in a small percentage (> 20%) of patients.2 In dogs with gastrointestinal pythiosis, survival is documented in only 2 dogs: 1 treated with partial gastrectomy and 1 recently treated medically with a combination of itraconazol, terbinafine, and mefanoxam.3–9
The patient described in the present report is unique because of the success of combined medical treatment, surgical treatment, and immunotherapy in a patient with chronic and advanced colonic pythiosis. Prior to definitive surgery, the disease had considerably progressed in the face of medical management. Surgical resection was extensive, but the distal margin was only 0.6 cm, much less than the 3 to 4 cm that is advised. Immunotherapy may have played a role in treatment of this patient, given the progression during preoperative medical treatment and the marginal surgical excision. However, because 3 treatment strategies were used in treating this patient, the efficacy of one of those treatments cannot be individually determined. In other studies,9,10 dogs with gastrointestinal pythiosis have not responded to immunotherapy with or without surgery or antifungal treatment; patients responsive to immunotherapy are restricted to those with cutaneous infections. Additionally, the patient of the present report was vaccinated approximately 2.5 months after the initial diagnosis. This timing is notable because of the reported poor efficacy of the vaccine in a small number of dogs with chronic (> 2 months) disease.10 The maximal benefit of immunotherapy is reported in animals with acute disease.10 The current vaccine available for treatment targets both exoantigens as well as cytoplasmic antigens of P insidiosum. The addition of cytoplasmic antigens appears to increase the vaccine's efficacy, especially in chronic pythiosis in horses, although reported case numbers are still quite small.10 Unlike horses, dogs generally do not have a robust clinical response to the vaccine, even in cases with a strong local vaccine reaction.10 In 1 study,10 only 2 of 6 dogs are reported to have responded to immunotherapy, compared with 13 of 18 horses. One of the 2 dogs was also treated with surgery, and the other was treated with antibiotics; both dogs had cutaneous lesions on the limbs. The reason for the worse response to vaccination in dogs, compared with that in horses, is unknown. In horses and people, both of which respond more favorably to the vaccine, declining IgG and IgE titers have been documented and correspond to a reduction in clinical signs of disease.10 It is theorized that the vaccine may cause immunomodulation and gain efficacy by shifting the host immune response from a T-helper type II cell response to a T-helper type I response.10 This hypothesis is supported by the reduction in IgE titers following vaccination as well as a shift in serum cytokines from interleukin-4 to interleukin-2. The decline in IgE titers and shifts in serum cytokines have not been reported in dogs.
In horses, a lack of a systemic response to previous versions of a pythiosis vaccine was predicted by negligible or weak vaccine site reactions.11 This relationship in dogs has not been documented.10 In the patient of the present report, a vaccine site reaction did not occur. Given the small number of cases in the literature and the fact that this dog received concomitant chemotherapy and surgery, it is impossible to determine the importance of a local vaccine reaction in dogs.
The diagnosis of pythiosis was made in our patient on the basis of histopathologic findings as well as positive results of an IgG ELISA. The latter has been described and evaluated in dogs and has a 100% specificity and sensitivity for pythiosis.1 Results of this assay are expressed as percent positivity in comparison with a strong positive control sample, with values > 40% positivity having been shown to be 100% sensitive and specific for canine pythiosis and values in healthy dogs ranging from 3% to 15%.1 Initial results in the patient of the present report were consistent with active pythiosis, with a percent positivity of 88%. The ELISA is useful not only as a screening diagnostic test, but also for monitoring response to treatment because a declining titer is indicative of a therapeutic response. The declining titers concomitant with vaccination suggested the antigenic epitopes used to determine which titers are distinct from, and do not cross-react with, those in the vaccine.
This report also highlights the considerable clinical undertaking in supporting dogs following the removal of a large amount of small intestine and a colectomy Following the second resection surgery, condition of the patient continued to decline until parenteral nutrition was initiated. Successfully returning the patient to an enteral diet required a slow, methodical refeeding plan both during hospitalization and following discharge from the hospital. The patient of the present report was constantly leaking fetid diarrhea for several weeks following surgery, and loose stools persisted chronically; however, the owner reported the dog could later hold feces for substantially longer periods of time and had an excellent quality of life. Short bowel syndrome occurs after removal of a large portion of the intestinal tract, and its occurrence is variable depending on the exact amount of bowel removed, the size of the patient, and whether the ileocecal (colic) valve or the colon was removed.12 Whereas this dog had only 40 cm of jejunum removed, an amount that would not normally predispose a dog to short bowel syndrome, the ileum, cecum, ileocecal valve, and colon were also removed. Clinically, the dog followed a course similar to that described for dogs with short bowel syndrome: initial severe diarrhea and steatorrhea occurred over the course of several weeks, with gradual intestinal adaptation and return to more normal function.12 Loss of the distal intestinal structures will predispose animals to absent bile acid and vitamin B12 absorption because of loss of the ileum. Additionally, reduced water and electrolyte absorption occurs because of loss of the colon. Intestinal transit time is reduced because of loss of the ileocecal valve, and the risk of small intestinal bacterial overgrowth is increased; however, rapid transit of ingesta through the remaining intestine may reduce bacterial ascension into the small bowel.12
Nutritional management of these patients is critical, and specially formulated, highly digestible low-fat diets are important. In the patient described in the present report, total parenteral nutrition was chosen to stabilize the patient until enteral feeding could be resumed. Although provision of nutrients into the gastrointestinal tract provides important trophic factors for intestinal adaptation following resection, this patient had become intolerant of enteral feedings and required short-term IV nutritional support to prevent worsening protein calorie malnutrition. Because of the history of vomiting with enteral feeds following the second resection surgery, water was selected for initial refeeding to evaluate tolerance of enteral feeds. Gradual introduction of more nutrient-dense diet ingredients progressed as the patient responded well to water, low-fat chicken broth, plain white rice, cottage cheese, and finally a low-residue commercial dry canine diet. Although very slow bolus feedings were chosen for this patient, a continuous rate of infusion of enteral nutrition could have been selected in the early refeeding period. In this case, tolerance to meal feeds needed to be established for home management of the patient prior to discharge from the hospital.
Because of the extent of intestinal resection, it was difficult to predict how well the remaining intestinal structures (duodenum and proximal jejunum) would adapt to enteral feeds in this patient. Protein, fat, and fiber; endogenous gastrointestinal tract secretions; and hormones are all important trophic factors for adaptation of the intestinal tract following resection. In this patient, resection of a large portion of the jejunum, ileum, ileocolic junction, and colon left a small segment of the small intestine to manage all nutrient digestion and absorption functions. Introduction of enteral feeds as soon as the patient can tolerate enteral nutrition is an important factor in improving intestinal adaptation following resection. In this dog, white rice and subsequent low-fat cottage cheese were chosen as introductory carbohydrate and protein sources because of the high digestibility, low residue, and low fat content. The initial response to this diet did not provide evidence of lactose intolerance in this patient. A balanced version of this diet was fed by the owner after the patient was discharged, prior to use of an Association of American Feed Control Officialsf–certified dry commercial canine low-residue and moderate-fat diet. Although intestinal adaptation can continue to occur for months following surgical resection, we suggest that it is likely that this patient will continue to have loose stool as a result of the loss of the colon. Alternatively, it is our clinical experience that Association of American Feed Control Officials–certified dry foods that are highly digestible and contain an alternate fiber source may slow gastric emptying, decrease fecal water, and bind bile salts in this patient and are future diet options. Continued treatment with parenteral vitamin B12 will also be necessary in this patient because of resection of the distal ileum, and periodic serum biochemistry analysis can be used to ensure normal electrolyte balance.
Anecdotally, removal of the entire colon in dogs is thought to result in a poor outcome. In the patient described here, the immediate outcome required intensive nursing care both at the hospital and after discharge. However, over time, the dog did very well and now lives a normal life. Recently, subtotal colectomy in 8 dogs has been reported.13 The ileocecal-colic junction was not removed in that series, and dogs returned to normal defecation approximately 7 weeks following subtotal colectomy. Colectomy is rarely indicated in dogs, and owners should be well aware of the expected postoperative clinical outcomes prior to surgery.
Gastrointestinal pythiosis is a difficult disease to treat and frequently results in a grave outcome. Veterinarians should have a high index of suspicion for this diagnosis when examining younger, outdoor dogs with anorexia and weight loss, especially if intestinal thickening is palpated or observed ultrasonographically and the patient lives in a warm, tropical environment. This patient is unique because, despite marginal excision, the dog appears to have recovered from the disease. In all cases, especially those with marginal excision, chemotherapy and immunotherapy should be considered as adjuvant treatment.
ABBREVIATION
| PEG | Percutaneous, endoscopically placed gastrostomy |
PDS II, Ethicon, Sommerville, NJ.
Precise 35W, 3M, Saint Paul, Minn.
Pan American Veterinary Labs, Hutto, Tex.
Purina Veterinary Diets HA Canine Formula, Société des Produits Nestlé SA, Vevey. Switzerland.
Hypoallergenic HP 19, Royal Canin USA Inc, St Charles, Mo.
Association of American Feed Control Officials, Champaign, Ill.
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