Histoplasmosis Infection in Two Cats From California
Systemic mycotic infections are typically localized to specific geographic regions of the country, because the organisms involved have certain environmental requirements for growth. Suspicion of infection relies on travel to or residence in recognized endemic regions. This report describes infection with histoplasmosis in two indoor cats from central California, an area not considered to be endemic for the disease. Systemic mycotic infections should be considered as differential diagnoses in any cat with compatible clinical signs, regardless of travel history or residence, especially if the cat is presented within a recognized endemic region.
Introduction
Systemic mycoses are relatively uncommon in cats compared to dogs, and regional prevalence of certain systemic fungal infections is well recognized. In this report, histoplasmosis was confirmed in two cats presented to a veterinary hospital located in the center of the San Joaquin Valley. The San Joaquin Valley is a region of California that is known for a high prevalence of Coccidioides immitis organisms. Both cats were born in the area, were housed indoors, and had never traveled out of the region. To the authors’ knowledge, this represents the first report of naturally occurring histoplasmosis in cats within a nonendemic region of California.
Case Reports
Case No. 1
A 9-year-old, 4.4-kg, spayed female ragdoll cat was presented in August 2001 to a local veterinary hospital for evaluation of gagging. The owner had obtained the cat as a kitten from a local breeder, and the cat was strictly an indoor cat within the urban region of Visalia, a city in the San Joaquin Valley midway between Fresno and Bakersfield, California. The cat had never traveled with the owner, there were no recent changes in the environment, and no previous illnesses had been noted. Physical examination revealed that the cat was febrile (104.6°F; 40.3°C) and had harsh inspiratory lung sounds. Ocular examination (including a retinal examination) was unremarkable. Symptomatic therapy with subcutaneous fluids (i.e., 100 mL lactated Ringer’s solution) and penicillin-G (20,000 units/kg intramuscularly [IM] q 8 hours) was employed initially. A complete blood count (CBC) revealed a white blood cell count of 10.2 × 103/μL (reference range, 5.0 to 18.9 × 103/μL) with a normal differential cell count. Serum biochemical profile revealed a low blood urea nitrogen (BUN, 13 mg/dL; reference range, 16 to 36 mg/dL). Thoracic radiographs delineated bronchointerstitial infiltrates that were most severe in the cranial lung lobes and perihilar region [Figure 1].
To determine the etiology of the pulmonary infiltrates, airway samples were obtained. The cat was anesthetized with isoflurane and intubated with a sterile red-rubber catheter. A tracheobronchial lavage was performed using 4 mL of sterile saline. Three mL of a dark, cloudy fluid was recovered and submitted to a commercial laboratorya and then later to the University of California Veterinary Medical Teaching Hospital (UCVMTH) for cytopathological evaluation. Direct, sediment, and cytospin slides were prepared and stained with Giemsa-Wright stain. Moderate to large numbers of predominantly macrophages and nondegenerate to degenerate neutrophils were noted. Macrophages often contained many small, oval, encapsulated organisms consistent with Histoplasma capsulatum (H. capsulatum) [Figure 2]. No cultures were performed.
Therapy with itraconazole liquid suspensionb was initiated (4.6 mg/kg per os [PO] q 12 hours) for treatment of pulmonary histoplasmosis. On recheck examination 10 days later, body weight had decreased to 4.0 kg, and the cat was still febrile (104°F; 40°C); however, the owner reported an improved attitude and appetite. Itraconazole was continued, and at the 6-week recheck, the owner reported that the cat was eating well and had regained a normal level of activity. On physical examination, the lung sounds were clear but weight loss had continued (3.4 kg).
Two months later, when the cat was presented for annual vaccination, the owners reported they had discontinued itraconazole 1 month previously. Total duration of therapy was 12 weeks. Physical examination was within normal limits, body weight had increased to 4.0 kg, and the owner declined thoracic radiographs. At this time, serum was submitted to both UCVMTH and a commercial laboratoryc for fungal serology. Agar gel immunodiffusion was negative for antibodies to H. capsulatum. Follow-up evaluation 1 year after the diagnosis was within normal limits. Blood work was not repeated.
Case No. 2
An 18-month-old, 2.4-kg, spayed female domestic shorthair cat was presented in January 2002 for evaluation of listlessness and ulcerative lesions on the face. The cat was originally found in the same city as a kitten, was an indoor cat, and had not traveled outside of the San Joaquin Valley. As with case no. 1, there were no recent changes in the environment, and commercial cat litter had been used throughout the cat’s life. The cat had lost weight (3.6 kg was the initial body weight) since a previous examination and was febrile (103.6°F; 39.8°C). Multiple nodular, pustular, and exudative dermatological lesions were noted around the left eye and bridge of the nose. Orbofloxacin (4.7 mg/kg PO q 24 hours) was prescribed for these lesions, but after 2 days the lesions had progressed significantly and retinal detachment was noted in the left eye [Figure 3]. Overt anterior segment inflammation was absent.
A CBC revealed a normal white blood cell count (9.0 × 103/μL) and a normal differential cell count. A serum biochemical profile revealed moderate hypoalbuminemia (2.0 mg/dL; reference range, 2.6 to 3.9 mg/dL). Because the skin lesions were similar to those reported in cats with coccidioidomycosis, a coccidioidomycosis titer was submitted to a commercial laboratorya and was negative.1 Multiple impression smears of the skin lesions were found to have many macrophages and markedly degenerate neutrophils. Macrophages contained high numbers of encapsulated organisms consistent with H. capsulatum [Figure 4]. Free yeast organisms were seen throughout the slide, and neutrophils were also found to contain organisms. Thoracic radiographs were normal, and no other organs were assessed for the presence of organisms.
Swabs of skin lesions were submitted for fungal culture to UCVMTH. Material was placed on inhibitory mold agar and incubated at 30°C in air. White, moist fungal colonies typical of histoplasmosis were noted on day 7. The isolate was then sent to the University of Texas Fungus Testing Laboratory to confirm the identity of the organism by use of a deoxyribonucleic acid (DNA) probe specific for H. capsulatum.2 This process utilizes a DNA probed labeled with an acridinium ester to complex with H. capsulatum ribonucleic acid (RNA) produced by the fungus. Nucleic acid hybridization of complementary pairs forms stable DNA:RNA hybrids that react with a chemiluminescent activator. A positive reading by the liminometer confirmed the culture as H. capsulatum. Serum was also submitted to a commercial laboratoryc for fungal serology, and agar gel immunodiffusion was negative for antibodies to H. capsulatum.
Therapy with itraconazole (5 mg/kg PO q 12 hours) was initiated for treatment of cutaneous and suspected ocular histoplasmosis. On a 3-week follow-up examination, the cat had an overall improvement in clinical demeanor; however, cutaneous lesions had enlarged and were more purulent, and the nose and facial region appeared swollen. After 4 months of continued itraconazole therapy, the skin lesions resolved, but mild swelling over the nose persisted. The cat was eating normally and had gained weight. Itraconazole was continued for an additional month, at which time the cat was normal in appearance, and the retinal detachment in the left eye had apparently resolved. To date the cat remains healthy.
Discussion
To the authors’ knowledge, infection with histoplasmosis has not been previously reported in cats that have been residents solely of California. The California state veterinary office has no prior reported cases of feline histoplasmosis localized to the state. Although histoplasmosis is the second most common systemic fungal infection in cats,3 most cases occur in animals living in endemic areas or in animals that have traveled to endemic regions of the country. In California, reported human cases of disseminated histoplasmosis are typically associated with reactivation of disease in individuals who have previously traveled to or lived in a histoplasmosis endemic region.45 The underlying source of histoplasmosis is presumed to be environmental in most instances.
Histoplasma capsulatum organisms proliferate in nitrogen-rich soil and prefer moist, humid environmental conditions. Soil that contains chicken, bird, or bat guano is an excellent medium for growth of Histoplasma organisms. In contrast to regions typical of histoplasmosis, the San Joaquin Valley is characterized by low environmental humidity, very low rainfall, and sandy, alkaline soil. Proliferation of organisms such as Histoplasma spp. would be unlikely in the natural environment and would require a protected environmental niche containing shade, higher humidity, and a primary source of fungal organisms.
Interestingly, 17 cases of histoplasmosis were diagnosed over a 7-year period in the dry, desert-like region of El Paso, Texas—an area similar to the San Joaquin Valley.6 Substantially more cats (n=15) than dogs (n=2) were affected, and in the cats, mortality was 87% (13 of 15 cats).6 Respiratory abnormalities were the most prevalent clinical signs noted. The Texas report established a microendemic region for H. capsulatum, with isolation of organisms from various soil samples taken from a bat cave 5 miles from the outbreak area as well as from regions near an abandoned chicken house.6 Soil testing for H. capsulatum organisms historically involved filtration techniques followed by intraperitoneal injections of mice with supernatant.7 In El Paso, isolation rates for H. capsulatum ranged from 20% to 100% of the soil samples collected.6 Soil sampling might have been useful in the cases reported here to establish a source of environmental exposure; however, the efficiency of culture methods for soil isolation is reportedly low. In addition, positive soil samples have been found on farms in the midwest that lack evidence of animal disease.7 More recently, detection of soil contamination with H. capsulatum has been achieved using a two-stage polymerase chain reaction.8 If this technique had been available for use in the cases described here, it would have provided the opportunity to investigate potential sources of environmental contamination with Histoplasma organisms.
Knowledge of the incubation period for regional diseases is important for considering possible exposure to various infective organisms, particularly in animals that travel to specific areas of the country. The incubation period for acute infection with H. capsulatum is approximately 12 to 16 days in humans and dogs,39 and it appears to be similar in the cat.6 The authors hypothesize that the two cats of this report were exposed to infective organisms in summer and late autumn, given the time when clinical signs were first reported. In contrast, in a large retrospective study of mycotic infections across the country, 50% of feline cases of histoplasmosis occurred between January and April,3 suggesting exposure to the organism during the winter months. In the dry, desert region of Texas where histoplasmosis was documented, the seasonal incidence of histoplasmosis was not investigated or reported. Conditions in hotter and more arid climates might allow for year-round exposure to organisms, or the epidemiology of disease may differ from that of recognized endemic regions.
The El Paso region of Texas in which histoplasmosis was documented was originally inhabited by chicken farmers and was extensively cultivated for crops. It became urbanized prior to the documentation of histoplasmosis, and it was theorized that excavation of the ground during large construction projects resulted in release of the Histoplasma organisms.6 It was also speculated that the degree of irrigation previously utilized in the region might have been sufficient to allow propagation of H. capsulatum in certain sheltered regions of the soil. It is possible that a similar microenvironment could be created in any region of the country, allowing propagation of unusual organisms in unexpected locations.
In the San Joaquin Valley during the months of July and August 2001, daily temperatures ranged from 85°F to 105°F (29.4°C to 40.6°C), with a mean of 94°F±5° (34.4°C±2.8°), and nightly temperatures ranged from 58°F to 78°F (14.4°C to 25.6°C), with a mean of 66°F±4° (18.9°C±2.2°).e A trace of rain was reported on July 7, 2002; however, the region is heavily agricultural, and parts of the area are extensively irrigated. Outlying regions that were previously used for growing crops and contained groves of walnut trees are currently being converted into areas of housing. It is possible that dormant fungal organisms in the soil were disrupted during excavation, leading to release of mycotic agents. However, it remains unclear how the cats of this report might have been exposed to a source of natural soil contamination. These cats were strictly indoor cats from separate households within established urban areas and resided within the city limits. They did live in an area known for poor air quality, which is polluted by smoke and particulate matter from the burning and clearing of old walnut groves. Aerosolization and dispersion of fungal spores could potentially have resulted in exposure to histoplasmosis in these cats, but the true source of infection remains a mystery.
Based on this and other reports,36 cats that are housed strictly indoors remain at risk for histoplasmosis. Indoor soil contamination was considered, but the cats reported here were not in contact with newly potted plants. It has previously been suggested that potting soil for indoor plants could serve as a source of Histoplasma infection.10 Identification of sources of exposure to fungal agents is of public health significance, because increasing numbers of systemic mycotic infections have been recognized, particularly in people with immune compromise from human immunodeficiency virus (HIV), and in people with malignancies and chronic lung disease.11 Concurrent infection of an owner and pet can occur with exposure to the same source of infective material,69 underscoring the importance of identifying systemic fungal infections in animals and investigating potential sources of infection.
The two cats of this report displayed different signs of histoplasmosis, with gagging in one cat and ocular lesions followed by extensive skin ulceration in the second. Thoracic radiographic abnormalities in case no. 1 were typical of pulmonary histoplasmosis.12 In case no. 2, severe ocular lesions preceded skin involvement, and there was a striking lack of anterior segment inflammation, which is characteristic of the ocular inflammation seen with fungal disease. Histoplasma capsulatum has previously been associated with granulomatous chorioretinitis and optic neuritis, indicating the organism has a predilection for the posterior segment of the eye.31314 Both of the cats reported exhibited a history of weight loss and were febrile, although other findings compatible with histoplasmosis, such as hepatosplenomegaly, lymphadenopathy, and anemia were absent. In a previous study, 23% of cats with histoplasmosis were documented to have concurrent disease, with the most common infection being feline leukemia virus (FeLV).3 No hematological abnormalities were noted in the cats of this report, and concurrent diseases were not detected. Both cats were negative for FeLV and feline immunodeficiency virus.
As with prior published cases, serology was not useful in the diagnosis of histoplasmosis in this report.36 A single serological test was performed in each cat during active illness, and this limited the authors’ ability to detect an antibody response; although convalescent sera was negative in case no. 1, and serum from case no. 2 submitted approximately 4 months after the onset of clinical signs was also negative. Importantly, in both cases, cytopathological specimens from the affected organ system were clearly positive for the small, intracellular yeast organisms of H. capsulatum. Both cats were successfully treated with itraconazole (5 mg/kg PO q 12 hours for 3 and 6 months), which has previously been shown to be efficacious in the treatment of histoplasmosis in cats.15 Historical reports of treatment responses in cats with histoplasmosis have described mortality rates of >66% when ketoconazole was used, so currently itraconazole is considered the superior therapy.36
Conclusion
Histoplasmosis can be encountered in endemic and nonendemic regions of the country. Veterinarians must be alert to the wide variety of clinical signs possible with various systemic fungal infections. In the cases reported here, histoplasmosis affected the respiratory tract, eyes, and integument. Identification of the intracellular organisms on cytopathological preparations from respiratory washes and skin impression smears provided a quick diagnosis of histoplasmosis.
IDEXX Veterinary Services, Irvine, CA
Sporanox; Janssen Pharmaceutica, Inc., Titusville, NJ
Protatek Reference Laboratory, Chandler, AZ
Accuprobe; Gene-Probe, San Diego, CA
Personal communication, Visalia Fire Department Record of River and Climatological Observations, 2002
Citation: Journal of the American Animal Hospital Association 40, 2; 10.5326/0400165
Citation: Journal of the American Animal Hospital Association 40, 2; 10.5326/0400165
Citation: Journal of the American Animal Hospital Association 40, 2; 10.5326/0400165
Citation: Journal of the American Animal Hospital Association 40, 2; 10.5326/0400165
Lateral thoracic radiograph from a 9-year-old rag-doll cat presented for gagging (case no. 1). Broncho-interstitial infiltrates are evident and are most severe in the cranial thoracic and perihilar regions of the lungs. The cardiac silhouette is within the reference range, and air is present in the stomach, probably from aerophagia.
Photograph of an 18-month-old domestic short-hair cat (case no. 2) showing ulceration of facial skin and the left eyelids from histoplasmosis. Blood vessels can be seen within the pupil posterior to the lens along with subtle leukocoria, indicating a retinal detachment.
