Cytologic Diagnosis of Disseminated Histoplasmosis in the Wall of the Urinary Bladder of a Cat

Introduction

Histoplasma capsulatum is a dimorphic saprophytic fungus that is most commonly diagnosed as a disseminated disease in dogs and cats.¹ The clinical signs of disseminated histoplasmosis in dogs and cats are variable and include lethargy, weight loss, fever, anemia, and anorexia.² The respiratory tree is often affected, and signs include coughing, difficulty breathing, tachypnea, and/or abnormal lung sounds. However, approximately 50% of all cats with pulmonary involvement have no respiratory signs. It is estimated that one-third of cats with disseminated disease have hepatomegaly, splenomegaly, or lymphadenopathy.³ Other sites of infection occasionally noted are the eye, skin, skeletal system, oral mucosa, small intestine, and central nervous system.^3–6 There are two recent case reports of disseminated histoplasmosis in cats from Europe and Japan, demonstrating that the disease is recognized globally.^7,8

A notable difference in the reports of disseminated histoplasmosis in cats and humans is the presence of genitourinary involvement. In people, the urinary tract has been reported to be involved in the infection.⁹ To the authors’ knowledge, involvement of the genitourinary system has not been reported in either cats or dogs with disseminated histoplasmosis. Genitourinary involvement has been reported in one dolphin, and hematuria was reported as a clinical sign in a retrospective study of feline cases but was never documented as involving the urinary system.^10,11

The purpose of this article is to report the diagnosis of disseminated Histoplasmosis via fine needle aspiration of the wall of the urinary bladder.

Case Report

A 10 yr old spayed female domestic longhair was referred to the Texas A&M Veterinary Medical Teaching Hospital with a 2.5 mo history of weight loss and recurrent hematuria. The primary veterinarian had previously noted that the urinary bladder was palpably thickened. The cat was prescribed amoxicillin trihydrate/clavulanate potassium^a (15 mg/kg per os [PO] q 12 hr for 7 days), and one injection of each of the following was administered: penicillin (21,739 U/kg), dexamethasone (0.1 mg/kg), and cobalamin (0.05 mg/kg). Two weeks after the initial visit to the primary veterinarian, the amoxicillin trihydrate/clavulanate potassium (15 mg/kg PO q 12 hr for 7 days) was repeated because the cat had not improved. The hematuria still did not resolve after the second course of antibiotics. Thirty days later, the primary veterinarian noted that the urinary bladder was still palpably thickened. Blood was observed in the urine toward the end of the urine stream following manual expression of the bladder. Abdominal radiographs taken at that time were normal. The cat was prescribed a third course of antibiotics (5.5 mg/kg enrofloxacin^b PO q 12 hr for 7 days) and amoxicillin trihydrate/clavulanate potassium (15 mg/kg PO q 12 hr for 7 days). A serum biochemistry panel at that time was within normal limits. One week later (5 wk after the initial presentation), the cat returned to the primary veterinarian for continued hematuria. An abdominal ultrasound examination at that time identified a uniformly thickened urinary bladder wall with a possible mass near the neck of the bladder. The cat was hospitalized for 1 wk for monitoring, continued enrofloxacin administration (5.49 mg/kg PO q 12 hr for 7 days), and a course of injectable dexamethasone (1.93 mg/kg subcutaneously q 12 hr for 5 days). The hematuria resolved by the end of that week, and the cat was discharged with a 10 day course of enrofloxacin (5.5 mg/kg PO q 12 hr).

Approximately 70 days after the initial onset of clinical signs, the cat presented to Texas A&M Veterinary Medical Teaching Hospital. The owner reported that the cat had become progressively more lethargic over the past 11 mo. The cat was kept predominantly outdoors. The cat's appetite was reported to be normal, and the owner noted no other signs of illness.

The cat was bright and alert on physical examination. A grade 2/6 systolic murmur with the point of maximal intensity over the left sternal border and a gallop rhythm were ausculted. Increased bronchovesicular sounds were also detected bilaterally on thoracic auscultation. The cat had a palpably thickened urinary bladder, and there was mild discomfort on abdominal palpation. The cat was in poor body condition (body condition score was 2/9), and a 5 mm right-sided thyroid nodule was also present. The remainder of the physical exam, including the fundic exam, was within normal limits. The fundic exam was performed with both direct and indirect ophthalmoscopy, and good visualization of the fundus was attained with no pupillary dilation.

A tabletop enzyme-linked immunosorbent assay for the feline leukemia virus (FeLV) p27 antigen and feline immunodeficiency virus (FIV) serum antibody^c was negative. A complete blood count and serum biochemistry profile were performed (Tables 1, 2). Urine sediment examination revealed hematuria (red blood cells [RBCs] too numerous to count/high-power field (HPF); reference range, 0 RBCs/HPF) and pyuria (15–20 WBCs/HPF; reference range, 0–5 WBCs/HPF). An insufficient amount of urine was obtained for additional diagnostic testing such as urine culture, protein electrophoresis, or a Histoplasma antigen test.

TABLE 1 Complete Blood Count

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TABLE 2 Biochemistry Profile

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A generalized bronchointerstitial pattern, flattening of the diaphragm, and hyperinflation of the lungs were identified on thoracic radiographs (Figure 1). Abdominal ultrasound examination identified a urinary bladder wall that was diffusely thickened, measuring 11 mm (reference range, 1–2 mm) at its thickest point. The wall was uniformly hyperechoic and lacked visible layering (Figures 2A, B). The mucosal surface of the urinary bladder was smooth. There was enlargement of the medial iliac and mesenteric lymph nodes, as well as enlarged, rounded lymph nodes adjacent to the neck of the urinary bladder. The spleen was enlarged and rounded, measuring 13 mm thick at the hilus (reference range, 5.1–9.1 mm). The right adrenal gland was enlarged and irregular, measuring 5 mm (reference range, 4.3±0.3 mm) in diameter. The left adrenal gland was not seen. A cystocentesis of the urinary bladder was performed; however, only 0.5 mL of urine was obtained due to the severely decreased lumen size.

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Multiple ultrasound-guided fine-needle aspirates (FNAs) of the spleen and urinary bladder wall were obtained. Results of the cytologic examination of the urinary bladder wall revealed moderate granulomatous inflammation with intralesional H. capsulatum organisms (Figure 3). Cytologic examination of the spleen demonstrated mild histiocytic inflammation with rare extracellular H. capsulatum organisms.

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Therapy for disseminated H. capsulatum infection was initiated once cytologic results were reported. The cat was prescribed itraconazole (10 mg/kg PO q 24 hr) for treatment of disseminated histoplasmosis and a subcutaneous injection of 250 μg of cobalamin q 7 days. Cobalamin was given as an adjunct to this patient's therapy based on data demonstrating a deficiency in clinically ill cats and little chance for iatrogenic harm.¹²

In a follow-up phone conversation 1 mo following discharge, the owner reported that it was difficult to medicate the cat, and no medical improvement was noted. The owner elected to humanely euthanize the cat. No necropsy was performed.

Discussion

H. capsulatum is a dimorphic, saprophytic fungus that has the highest prevalence in the United States in the Ohio, Mississippi, and Missouri river valleys, although it may occur in any temperate climate.¹ Cases also have been identified outside previously reported endemic areas.^4,7,8,13 Soil with a rich nitrogen source (e.g., from avian or bat feces) is favorable for growth of the organism as it facilitates sporulation of the fungus in the environment.¹⁴

This fungal organism exists in the soil in mycelial form and in the body of the host as yeast.¹ Infection occurs by inhalation or ingestion of the sporulated fungal microconidia from the environment.³ Once in the host, the microconidia transforms to the yeast phase. The yeast is phagocytized by macrophages and may be disseminated via lymphatic and hematogenous circulation.¹ A 12–16 day incubation period after exposure has been estimated in dogs and humans.³ The incubation period in cats is likely similar, but has not been reported. The cat in this case report was a predominately outdoor cat and was almost certainly exposed to H. capsulatum in the environment, although the source of the exposure is unknown.

Most infections in companion animals are subclinical.¹ Clinical disease usually results either when the infective dose of spores is large or in immunosuppressed hosts with poor cell-mediated immunity. The cat in this report did not have a known pathologic cause of immunodeficiency.

Cats with disseminated histoplasmosis are typically <4 yr old.³ Clinical signs exhibited by cats with disseminated disease are nonspecific and include lethargy, weight loss, fever, anemia, and anorexia.² The cat in this report exhibited weight loss. Respiratory signs usually include dyspnea, tachypnea, and/or abnormal lung sounds. Coughing is rare, and approximately 50% of cats with pulmonary involvement have no respiratory signs.³ The patient described in this report had increased bronchovesicular sounds but no dyspnea or tachypnea on physical examination. Thoracic radiographs revealed a bronchointerstitial pattern that could be consistent with the presence of a Histoplasma infection in the lungs. Other differentials for harsh lung sounds include asthma, chronic obstructive pulmonary disease, and other small airway diseases. Neither the lung parenchyma nor airways were sampled.

It is estimated that one-third of cats with disseminated disease have hepatomegaly, splenomegaly, or lymphadenopathy.³ The abdominal ultrasound examination of this patient identified splenic enlargement and multiple enlarged lymph nodes. Other sites of infection occasionally noted are the eye, skin, skeletal system, oral mucosa, or the small and large intestine.^3–5 Although not common in dogs, dissemination to the small intestine has been reported in cats.^5,7,8 Nervous system involvement in the cat and dog is rare, although it has recently been reported in the spinal cord of one cat.⁶

Common hematologic abnormalities in cats with disseminated histoplasmosis are nonspecific and include nonregenerative anemia, neutrophilia, monocytosis, and/or eosinopenia.¹ Leukocytes containing phagocytized yeast organisms may be found in peripheral blood smears or buffy coats. Biochemical abnormalities reported in cats with disseminated disease may include hypoalbuminemia, hyperglobulinemia, hyperproteinemia, and mildly increased alanine aminotransferase activities. Most cats are not concurrently infected with either FeLV or FIV.¹ In this case, there was mild hyperglobulinemia, a mild decrease in alanine aminotransferase, and no evidence of either FeLV or FIV.

Histoplasmosis is definitively diagnosed in cats by either cytologic or histopathologic identification of the yeast organisms.¹ In cats, samples that are commonly obtained for identification of the yeast are lymph nodes, bone marrow, spleen, liver, and (rarely) fluid from a bronchoalveolar lavage.² There is currently no diagnostic test available that utilizes serology to identify histoplasmosis in companion animals.¹ The treatment of choice in cats is long-term itraconazole therapy, typically for 4–6 mo at 10 mg/kg q 24 hr. Response to therapy or relapse are determined by monitoring appetite, weight gain, and resolution of clinical signs.¹⁵ To the authors’ knowledge there is not currently a diagnostic test used in companion animals to monitor progression of disease.

A promising diagnostic test for histoplasmosis is a real-time polymerase chain reaction assay. A commercial test for the detection of DNA specific to H. capsulatum^d is currently available. Whole blood, pharyngeal swabs, tracheal washes, aspirates, or biopsies of masses, ocular aspirates, cerebral spinal fluid, feces, tissue, or bone aspirates can be tested. There is little literature supporting the routine use of polymerase chain reaction to detect Histoplasma, but the availability of the test will likely change that in the future.

There are several interesting similarities between human and companion animal cases of disseminated histoplasmosis due to infection with H. capsulatum. These include the clinical signs seen with disease, the signalment of the patients, and the disease course. Many infected people either have no symptoms or only a localized respiratory infection. Association with an immunodeficiency virus has not been identified in cats.² People that are immunocompetent or are younger may have a chronic and progressive clinical course of disseminated histoplasmosis. In this form, clinical signs are often nonspecific and include anorexia, fever, fatigue, night sweats, and respiratory signs.¹¹ Cats with histoplasmosis usually have disseminated disease, often have nonspecific clinical signs, and a chronic progressive disease course.¹ Additional findings commonly noted in humans with chronic progressive disseminated histoplasmosis are lymphadenopathy, hepatomegaly, and splenomegaly. Of human patients with disseminated histoplasmosis that undergo abdominal ultrasound or computed tomography, over half have adrenal involvement.¹¹ The cat in this case had an enlarged, irregular adrenal gland noted on abdominal ultrasound, the significance of which is unclear.

One contrast between human and feline histoplasmosis is the method by which the infection is diagnosed. In companion animals the diagnosis is usually made by identification of the yeast on either cytology or biopsy samples of an affected organ.² In people the diagnosis is often made by testing for Histoplasma antigen in the urine, which is present in 90% of patients with disseminated infection. Falling urine antigen levels indicate a response to treatment, and relapse is associated with a rise in antigen levels, occurring even before clinical signs recur.¹¹

Although the human H. capsulatum antigen test has been used in cats and dogs by some veterinary clinicians, the test has not been validated in either cats or dogs. Disseminated histoplasmosis diagnosed by antigen detection has only been reported in one veterinary case involving a bottlenose dolphin.¹⁰ Fungal cultures for histoplasmosis have inherent disadvantages that make their use clinically cumbersome, and the health risk to laboratory personal is problematic. FNA cytology of tissue is relatively inexpensive and noninvasive, but the yeasts are sometimes difficult to detect when present in low numbers. Biopsy of affected tissues can provide a definitive diagnosis but is invasive and often requires patients with compromised health to undergo either anesthesia or sedation. If a validated H. capsulatum antigen test was readily available for companion animals, the need for more invasive methods of testing could be reduced. Additionally, antigen levels in urine could be monitored to identify either response to therapy or relapse in feline patients. Urine antigen testing is used in the diagnosis of other fungal diseases. For example, the diagnosis of blastomycosis by a urine antigen enzyme immunoassay has been reported in dogs.¹⁶

This report is limited by the absence of a necropsy to establish the extent of urogenital involvement and other lesions. However, the diagnosis was definitively made via a FNA of both the urinary bladder and spleen. Ideally H. capsulatum antigen testing would have been performed, providing a comparison with the disease in humans. If validated in cats, routine H. capsulatum antigen testing of the urine may be warranted on suspected cases. In addition, a urine culture was never performed on the cat described in this report; therefore, a concurrent bacterial urinary tract infection could not be ruled out.

Disseminated histoplasmosis should be considered for cats residing in endemic areas with clinical signs referable to the urinary tract, hematuria, or thickening of the urinary bladder wall. The potential for diagnosis and monitoring of this disease by urine antigen testing exists, which may be most useful for suspected cases where the yeast is not readily identified with either cytologic or histologic examination.

Conclusion

Disseminated Histoplasmosis is not an uncommon disease in various parts of the country. While there have been cases of disseminated Histoplasmosis diagnosed involving the urogenital system in other species, to the author's knowledge, this is the first reported case of disseminated histoplasmosis involving the urinary bladder wall in a cat.