A 9-year-old neutered male domestic shorthaired cat had been presented to the referring veterinarian for evaluation of lethargy and weight loss.
A 9-year-old neutered male domestic shorthaired cat had been presented to the referring veterinarian for evaluation of lethargy and weight loss. The cat lived exclusively outdoors and had been vaccinated twice in the previous three years (the last time being six months before presentation) against rabies, feline viral rhinotracheitis, feline caliciviral infection, chlamydiosis, and feline panleukopenia. The owners were able to observe the cat daily when it came to the house to be fed. A complete blood count and serum chemistry profile had revealed anemia (hematocrit = 16.6%; reference range = 24% to 45%), hypoalbuminemia (2.05 g/dl; reference range = 2.6 to 3.9 g/dl), hyperglobulinemia (6.29 g/dl; reference range = 2.8 to 5.1 g/dl), and an elevated total white blood cell count (28.3 × 109/L; reference range = 5 to 18.9 × 109/L). The referring veterinarian had prescribed clindamycin, and the cat had improved.
Four months later, the cat had been presented to the referring veterinarian because of constant vocalization and severe abdominal distention. The owners had noticed that the cat had become increasingly lethargic and anorectic and was vomiting. The results of a complete blood count and serum chemistry profile had been similar to those before except for a further increase in the total white blood cell count. At both visits to the referring veterinarian, the results of enzyme-linked immunosorbent assays (ELISAs) had been negative for feline leukemia virus (FeLV) antigen and feline immunodeficiency virus (FIV) antibody. The cat was subsequently referred to The University of Tennessee's College of Veterinary Medicine for evaluation of severe abdominal distention.
On initial physical examination, the cat was depressed and emaciated, weighing 4.6 lb (2.1 kg). It was hypothermic, with a rectal temperature of 94.5 F (34.7° C). The cat's heart rate was 150 beats/min, and its respiratory rate was 24 breaths/min. The cat's mucous membranes and sclerae were mildly icteric, and the cat was estimated to be 7% to 10% dehydrated. A grade II/VI systolic murmur was auscultated at the left sternal border; lung sounds were normal bilaterally. Femoral arterial pulses were palpably weak. The cat's abdomen was greatly distended and tympanic when percussed. Subcutaneous emphysema was present bilaterally along the dorsal aspect of the caudal thorax and cranial abdomen. Diffuse ulceration was present on the tongue's dorsal surface. An ophthalmologic examination revealed severe chorioretinitis in the left eye and a collapsed globe, a collapsed uvea, hyphema, and a hypermature cataract in the right eye. Initially, we suspected that the subcutaneous emphysema and abdominal distention were due to the free gas in the abdomen. Initial supportive care was instituted and included intravenous fluid administration while diagnostic tests were being done.
Laboratory Test Results
Abnormal complete blood count results included a nonregenerative, hypochromic anemia; leukocytosis; neutrophilia with a mild left shift; and lymphopenia (Table 1). Serum chemistry profile abnormalities included an elevated blood urea nitrogen concentration, hypoalbuminemia, hyperglobulinemia, hyperbilirubinemia, mild hyponatremia, and elevated aspartate transaminase activity (Table 1). A urine sample was not obtained at initial presentation because of the cat's tympanic abdomen and suspected pneumoperitoneum. The results of FeLV and FIV ELISAs were negative. The result of an ELISA for Dirofilaria immitis antibody was negative, and the result of an ELISA for D. immitis antigen was weakly positive. An IgM antibody titer for Toxoplasma gondii was less than 1:512 (greater than or equal to 512 is suspect), and the IgG antibody titer was 1:8,192 (greater than or equal to 32 is considered positive). A Western blot to detect antibody to Bartonella henselae, Bartonella clarridgeiae, and Bartonella koehlerae measured +3 (immunoblot grade = +1 to +4), indicating strong reactivity and possible infection.
Thoracic radiographic findings included dense interstitial opacities throughout all lung fields, a moderate amount of bronchial thickening, and an alveolar infiltrate within the ventral lung fields (Figures 1A & 1B). Because of the severe mixed pulmonary pattern, we suspected a chronic inflammatory lung disease. Abdominal radiographic findings included a large amount of free gas in the peritoneal space, which enhanced the visibility of the serosal margins of all abdominal structures (Figures 2A & 2B). Our primary differential diagnosis for the pneumoperitoneum was a gastrointestinal perforation because of the absence of a penetrating abdominal wound on physical examination, so we treated the case as a surgical emergency.
Figure 1A: A right lateral thoracic radiograph demonstrating a diffuse interstitial to alveolar pattern with bronchial thickening.
The abdomen was prepared for abdominocentesis, and 735 ml free air was removed with a butterfly catheter attached to a syringe by a three-way stopcock. The patient was subsequently premedicated with butorphanol tartrate and diazepam, followed by isoflurane mask induction for an exploratory celiotomy. Intravenous fluid support consisted of 5 ml/hr of a balanced electrolyte solution (Normosol-R—Abbott Laboratories) with 5% dextrose added and polymerized bovine hemoglobin solution (Oxyglobin—Biopure; 75 ml over two hours) to maintain adequate perfusion and tissue oxygenation.
We found a 1-cm perforation in the cardia of the stomach (Figure 3). Intraoperative cytologic examination of a sample of the affected area revealed normal gastric epithelium. The gastric mucosa surrounding the perforation was grossly normal. We resected a full-thickness 1-x-4-cm area surrounding the defect and submitted it for histologic examination. We saw no other abnormalities intraoperatively throughout the abdomen, and the defect and abdomen were closed in a standard manner. The gastric mucosa was later found to be normal in all biopsy sections.
Figure 1B: A ventrodorsal thoracic radiograph demonstrating a diffuse interstitial to alveolar pattern with bronchial thickening.
Because of the radiographically severe respiratory disease, we performed a transtracheal wash through the endotracheal tube immediately after the surgery and before extubation. Five milliliters of sterile saline was injected twice through a sterile catheter. The recovered fluid was centrifuged, and cytologic examination revealed moderate numbers of normal ciliated columnar epithelial cells. No microorganisms or inflammatory cells were noted.
Postoperatively, the patient had a severely decreased packed cell volume of 9%, so we performed a transfusion (based on a prior crossmatch) consisting of 25 ml packed red blood cells. Cefazolin sodium (50 mg intravenously t.i.d.) was administered during surgery and was continued along with enrofloxacin (11 mg intravenously b.i.d.) to achieve broad-spectrum antibiotic coverage. We continued clindamycin administration (25 mg orally b.i.d.) because of possible T. gondii infection.
Figure 2A: An abdominal radiograph showing a large volume of free gas within the peritoneal space, enhancing the visibility of the serosal surfaces of the abdominal organs.
The cat seemed to improve over the next 12 hours, but within 24 hours its condition declined. It became depressed and weak, and its temperature increased from 99.5 F to 102.6 F (37.5 C to 39.2 C). We performed a diagnostic peritoneal lavage by infusing 22 ml/kg warm isotonic fluid into the abdomen. Recovered fluid contained mature neutrophils and occasional macrophages, which we attributed to the celiotomy performed the previous day. The cat became progressively more depressed, and its breathing was labored, so we transferred the cat to an oxygen cage maintained at a 40% oxygen concentration. The cat subsequently developed respiratory arrest followed shortly by cardiac arrest. Cardiopulmonary resuscitation was unsuccessful, and the cat died.
At necropsy, a large 1-x-2-cm ulcer was present on the dorsal surface of the tongue, and ulcers were present on the hard palate. Histologic examination of the tongue revealed chronic, focal ulceration. The surgical site on the lesser curvature of the stomach was intact. Histologic examination of the area immediately surrounding the suture line showed that it contained neutrophils, lymphocytes, and macrophages. Scattered, perivascular infiltrates of lymphocytes and plasma cells were present in adjacent gastric mucosa, which is consistent with gastritis. Petechiae were observed on the serosal surface of the jejunum, and melena was present within the lumen.
Figure 2B: An abdominal radiograph showing a large volume of free gas within the peritoneal space, enhancing the visibility of the serosal surfaces of the abdominal organs.
The lungs contained multiple firm nodules. Pulmonary histologic findings included a severe, multifocal, subacute to chronic bronchopneumonia with bronchiectasis and a more acute necrotizing bronchitis. The pneumonia was characterized by interstitial lymphocytic infiltrates and fibrosis. Lymphocytic infiltrates and fibrosis were also observed on histologic examination of the liver.
Infectious agents, including T. gondii, were not evident in sections stained with hematoxylin-eosin or Gram's stain, and modified Steiner silver stain failed to reveal Bartonella species in any of the necropsy samples. However, Gomori's methenamine silver stain revealed fungal organisms in many tissue samples. In most locations, fungi were yeast forms up to about 8 µm in diameter with narrow-based budding, but septate hyphae were also present in the bronchial debris along with budding yeast. Yeast organisms were almost always found in areas of inflammation, including the liver, alveolar parenchyma of the lung, and both eyes, and were particularly numerous in the adrenal medulla. Rare hyphae and yeast were present in superficial and deep sections of the tongue.
Figure 3: The gastric perforation intraoperatively.
The morphology of the fungi in sections stained with Gomori's methenamine silver was most consistent with Candida species (Figure 4), and identification was confirmed by the results of a germ tube test performed at The University of Tennessee College of Veterinary Medicine Clinical Bacteriology/Mycology Laboratory. The germ tube test is a simple, rapid procedure that is used for the presumptive identification of Candida albicans.1 The test was performed by inoculating colonies into a tube containing 0.5 ml sterile horse serum (GIBCO cell culture products—Invitrogen, Carlsbad, Calif.) and incubating the tube at 98.6 F (37 C) up to four hours. The incubated material was examined under a microscope for germ tubes or true hyphae, which must be distinguished from pseudohyphae. Candida albicans was demonstrated in necropsy samples of the spleen, liver, alveolar spaces and bronchi of the lung, interstitium of the kidney, adrenal medulla, posterior chambers of both eyes, bone marrow, and mesenteric lymph nodes. Organisms were not identified in the brain, another organ affected in patients with disseminated candidiasis.2,3
Pneumoperitoneum is an accumulation of free air or gas within the peritoneal cavity. Frequent causes of pneumoperitoneum in dogs and cats include trauma from perforating wounds and motor vehicle accidents, gastrointestinal perforation from neoplasia, gastric ulceration and perforation from the use of nonsteroidal anti-inflammatory drugs and glucocorticoids, and iatrogenic air introduction during surgery.4,5 Reports of cats with pneumoperitoneum have documented gastric perforation from penetrating ulcers and gastrointestinal lymphoma.6-9 The cat in this report had been chronically ill, and a gastric perforation from a focal ulcer was the most likely cause. None of the documented causes of gastrointestinal ulceration, including neoplasia or the use of nonsteroidal anti-inflammatory drugs and glucocorticoids, were present in this cat. However, in a previous report, 35% of patients had pneumoperitoneum due to gastrointestinal perforation without an underlying cause.4 In a recent retrospective report of dogs and cats with gastrointestinal perforation, cats were found to conceal their illness four times longer than dogs.10 All reported cases had concurrent disease, and most had prolonged illness before diagnosis and treatment.10 Pneumoperitoneum is treated by performing a surgical exploratory to identify and correct the underlying cause.
Figure 4: Hyphae and narrow-based budding yeast (inset) morphologically consistent with Candida species are present in the bronchial exudate and debris (Gomori's methenamine silver stain; 400X [inset 1,000X] original magnification).
A second problem in this cat was disseminated candidiasis. The mucosal barrier is the first line of defense against fungal organisms, and cell-mediated immunity is important in the suppression and control of fungal infections once they become systemic. Both the oral ulcers and gastric perforation in this cat allowed for a breakdown in the mucosal barrier and were the most likely points of origin for C. albicans. Candida albicans is an opportunistic pathogen. It is a dimorphic organism normally found on the mucosal surfaces of the proximal gastrointestinal and distal urinary tracts and is rarely isolated from the soil. The histologic identification of the yeast and hyphal forms of C. albicans within the respiratory tract of this cat is definitive evidence of dissemination. Numerous hyphae were isolated from the bronchi and alveolar spaces, and pulmonary candidiasis in people is associated with a 70% mortality rate.11 The yeast to hyphal transition of C. albicans has been associated with the production of fungal exotoxins and can lead to septic shock, which may have been one of the reasons for this cat's sudden decompensation and subsequent death.12 Additionally, the large amount of yeast present within the adrenal medulla may have led to adrenal hypofunction and postoperative decompensation. Further support of adrenal hypofunction included the cat's vague signs of anorexia, vomiting, and lethargy together with a leukocytosis, nonregenerative anemia, and mild azotemia. The high normal potassium and low sodium concentrations in an anorectic, dehydrated patient were further evidence of this possibility. Treatment for candidiasis includes administering antifungal medications (amphotericin B or imidazoles such as ketoconazole, itraconazole, or fluconazole), but once the candidiasis is disseminated, the prognosis is guarded.13
Reported factors leading to candidiasis in people and animals include immune suppression, neoplasia, chemotherapy, prolonged antibiotic or glucocorticoid use, diabetes mellitus, burns, infectious disease, and prolonged intravenous or urinary catheter placement.13,14 Multiple factors may have contributed to disseminated candidiasis in this cat, including the oral ulceration and gastric perforation that represented a break in mucosal defenses. Additionally, the cat had received broad-spectrum antibiotics in the recent past that may have inhibited resident microflora, allowing C. albicans to proliferate in the gastrointestinal system. Candidiasis in cats has been associated with gastroenteritis, pyothorax, diabetes mellitus, urocystitis, and uveitis.2,15-18 Ocular and systemic candidiasis was documented in two cats that had negative test results for FIV and FeLV, as was the case in this cat.2,18 Although FIV and FeLV cannot be completely ruled out based on serology, the ELISA is considered a sensitive test, so it was unlikely that either of these was a contributing factor in this cat.19 Candida albicans is the most frequently isolated fungal pathogen in immunocompromised people14; however, the cat in this report had evidence of an active immune system supported by a leukocytosis. The white blood cell count was elevated at each examination, suggesting that the cat was not immunosuppressed. In fact, a leukocytosis was a common finding in cats reported to have candidiasis.2,16-18 Multiple clinicopathologic abnormalities in this case could be attributed to chronic inflammatory disease, including the neutrophilia, lymphopenia, and hyperglobulinemia. A mild left shift can be associated with an infection but can also be part of a chronic inflammatory condition or granulomatous disease.
Other clinicopathologic abnormalities included an elevated blood urea nitrogen concentration, which may have been due to azotemia (prerenal or renal) but was more likely due to blood in the gastrointestinal tract, as was seen during necropsy evaluation. Gastrointestinal hemorrhage may lead to increased absorption of protein and subsequent elevation in blood urea nitrogen. The normal creatinine concentration might have been inappropriately low because of the cat's emaciated condition and associated loss of lean muscle mass.20 The icterus and hyperbilirubinemia were most likely due to hepatic or posthepatic causes, since no hemolysis was observed and severe lymphocytic infiltrative hepatitis with fibrosis and biliary hyperplasia were noted on histologic examination of the liver. It is not clear why the liver enzyme activities were normal in the face of obvious histologic abnormalities. Because the liver enzymes evaluated (alkaline phosphatase and alanine aminotransferase) are inducible or leakage enzymes, not tests of liver function, measuring bile acids or blood ammonia concentrations may have been beneficial in this case.
We never definitively diagnosed toxoplasmosis in this cat. Because toxoplasmosis can be difficult to diagnose, a combination of serologic test results and clinical signs is often required. Serologic tests for T. gondii, a protozoal organism, measure detectable antibody to IgM and IgG. Current or recent infection is generally suspected when there is an elevated IgM titer or at least a fourfold increase in IgG titers with paired serum samples.21 Cats can have persistently elevated IgG titers years after exposure; consequently, the single elevated IgG titer for T. gondii in this cat may not have been evidence of current infection.21 Convalescent serum was not available for evaluation. Ocular lesions such as chorioretinitis and anterior uveitis are common manifestations of toxoplasmosis.22 Most lesions consist of a lymphocytic-plasmacytic infiltrate without identifiable organisms, as was the case in this cat. We thought that the elevated IgG titer combined with the clinical signs consistent with T. gondii infection, including pulmonary disease and chorioretinitis, warranted appropriate antibiotic therapy even if the organisms were not identified.
The positive result on the Western blot for Bartonella species antigen in our patient was suggestive of Bartonella species exposure. Cats that test +3 or +4 are considered to be currently infected, and appropriate antibiotic therapy is recommended.23 Multiple studies have suggested that bartonellosis can lead to chronic disease, and simultaneous infection with T. gondii and Bartonella species may be required to observe more pronounced disease manifestations.24 Although bartonellosis was not confirmed with a positive blood culture result or by polymerase chain reaction testing, it is a disease with vague historical and clinical signs such as those observed initially in this cat, so we initiated appropriate treatment.
We performed heartworm antibody and antigen testing in this cat because of the radiographic evidence of respiratory disease. A diagnosis of feline heartworm disease requires multiple testing modalities for accurate diagnosis. A positive antibody test result correlates with exposure to D. immitis, and a positive antigen test result correlates with infection. Ideally, the positive antigen test result in this case would have been followed with an echocardiographic examination, which reportedly detects heartworms in cats with a sensitivity of 78%,25 but further workup was precluded by the need for emergency surgery. We attributed the murmur in this cat to chronic anemia since no cardiac abnormalities were noted on necropsy.
In complicated cases such as this, not only is it imperative to address immediate problems, but it is equally important to methodically evaluate every aspect of the case to appropriately manage each problem. Although the cat in this report was presented for the obvious problem of abdominal distention and it had a gastric perforation, the disseminated candidiasis and severe underlying respiratory disease were life-threatening comorbidities that played an important role in patient management and eventual outcome.
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