Abstract
Feline histoplasmosis is a systemic fungal infection often treated with itraconazole, which can be cost-prohibitive for some clients. Additionally, although the clinical disease in cats has been documented, sources of Histoplasma species spore exposure in cats have yet to be thoroughly investigated. The objectives of this study were to compare the outcomes of cats with histoplasmosis treated with fluconazole to those treated with itraconazole, and to evaluate possible sources of exposure for affected cats. Medical records from feline patients with confirmed histoplasmosis (n = 32) at Kansas State University were systematically reviewed and follow-up was performed by owner telephone interview. Cats treated with fluconazole (n = 17) had similar mortality and recrudescence rates when compared with cats treated with itraconazole (n = 13). Thus, fluconazole may be a viable alternative therapy for the treatment of feline histoplasmosis. Eleven cats were housed strictly indoors and possible sources of exposure reported for these cats included potted plants (5/11) and unfinished basements (6/11).
Introduction
Histoplasma capsulatum is a saprophytic dimorphic fungus commonly found in the central United USA, particularly near the Missouri, Mississippi and Ohio River valleys. Exposure usually occurs via inhalation, although ingestion has been proposed as an alternate route of entry. In soil, the fungus exists in a mycelial form; however, at mammalian body temperatures, it converts into a yeast. Yeasts survive intracellularly, specifically within cells of the mononuclear system. Trafficking of infected monocytes from the lungs to other organs of the body leads to dissemination of the organism and systemic histoplasmosis. 1
Feline histoplasmosis is second only to cryptococcosis as the most commonly diagnosed systemic mycosis in cats. 2 Previous studies have reported that young cats are most often affected.2,3 No sex predilection has been reported, although one study suggested that Persian and Siamese breeds may be over- and under-represented, respectively. 2 Although the pathogenesis of histoplasmosis may suggest that outdoor cats have a higher risk for developing disease because of exposure to contaminated soil, infection in strictly indoor animals has been reported. 4 Indoor/outdoor status and possible sources of exposure for feline histoplasmosis have yet to be critically evaluated. Clinical signs of feline histoplasmosis most commonly include non-specific, generalized signs, such as lethargy, anorexia, fever and weight loss present in 67–85% of cats, and respiratory signs, such as coughing, tachypnea and dyspnea (39–93% of cats).2,3,5,6 Lymphadenomegaly, cutaneous masses, chorioretinitis and uveitis are also common. Myelopathy and osteomyelitis are uncommon, but have been reported.7,8
Histoplasmosis is most commonly diagnosed by identification of the fungal organism by cytology or histopathology of tissues and fluids. The organism appears as a small (2–4 μm diameter) yeast with a thin, clear rim. Organisms are usually found intracellularly as multiples, but occasionally exist as singlets and extracellularly. 9 Serologic testing for histoplasmosis is available in cats but has a high rate of false-positive and false-negative results and thus has limited clinical utility, particularly in acute infection. 10 A third generation enzyme-linked immunosorbent assay (ELISA) for detection of Histoplasma species antigen (MiraVista) is sensitive and specific (94% and 100%, respectively) in feline urine and serum. 11 However, in humans, high cross-reactivity with Blastomyces dermatitidis, Coccidioides immitis, Paracoccidioides brasiliensis and Penicillium marneffei has been reported. 12
Azole antifungal drugs are the mainstay of treatment for feline histoplasmosis. Successful therapeutic outcomes have been reported with both ketoconazole and itraconazole.3,5,6 Itraconazole has been recommended as the standard of care in both human and veterinary medicine, and is more efficacious and has fewer adverse effects than ketoconazole.1,10,13,14 However, the use of itraconazole may be cost-prohibitive for some clients. Additionally, not all cats respond well to treatment with itraconazole, and side effects, particularly hepatotoxicity, are reported.5,15 Use of fluconazole, another azole antifungal drug, for the treatment of feline histoplasmosis has not been reported extensively in the literature. 5 Adverse effects of fluconazole are not well documented, but can include gastrointestinal upset and hepatotoxicity. 16 Anecdotally, fluconazole appears to have good efficacy against Histoplasma species in cats and is less expensive than itraconazole. Thus, fluconazole is an alternative therapeutic choice for feline histoplasmosis that is more cost-effective.
The objectives of the study presented here were twofold. The first objective was to compare the outcomes of cats with histoplasmosis treated with fluconazole with those treated with itraconazole. The second objective was to evaluate possible sources of exposure to Histoplasma species spores in the environment in feline patients from the Kansas State University Veterinary Health Center (KSU-VHC) with confirmed histoplasmosis.
Materials and methods
Medical records at the KSU-VHC were searched using the Veterinary Medical Database from January 2004 to September 2011 for cats with a diagnosis of histoplasmosis. Search terms included ‘Histoplasma’, ‘histoplasmosis’ and ‘fungal pneumonia’. Cats presented during that time for recheck evaluation with an initial diagnosis of histoplasmosis made prior to January 2004 were also included. Animals were included if cytology or histopathology confirmed the diagnosis of histoplasmosis.
Information regarding signalment, history and physical examination findings were obtained from each record. Results from clinicopathologic evaluation, imaging, histopathology, necropsy and other diagnostic tests were recorded where available. Treatment type, dose and duration were also recorded where applicable. Follow-up information was obtained from the medical record, from referring veterinarian records with owner permission and by owner contact. For the purposes of follow-up, clinical resolution was defined as cessation of clinical signs and either resolved radiographic changes or radiographic changes consistent with inactive lesions. Recrudescence was defined as recurrence of clinical signs with radiographic evidence or other diagnostic findings consistent with histoplasmosis. Owners were contacted via telephone for follow-up information; additionally, owners were asked to participate in a survey by telephone regarding possible sources of exposure to Histoplasma species spores. The investigated possible sources focused on exposure to soil (indoor/outdoor status and access to potted plants, construction and unfinished basements) and exposure to feces of possible carrier animals (bats, pigeons, chickens). Although not a source of exposure, possible concurrent human exposure and infection were also investigated. Cats that spent part of the time indoors and part of the time outdoors were considered to be outdoor cats for the purposes of the survey.
Continuous data were expressed as a median and range. Data from bloodwork provided by referring veterinarians were included in percentages of hematologic and biochemical abnormalities, but not in median and range calculations. Categorical data (survival and recrudescence) were compared using the Fisher’s exact test. Continuous data (disease-free interval) were compared using the Wilcoxon rank sum test. Statistical analyses were performed using commercial software (Microsoft Excel). A P value of <0.05 was considered to be significant.
Results
Study cohort
Thirty-two animals were included in this study. Two of these 32 cats were euthanased prior to treatment and were excluded from analysis of mortality and recrudescence. The median age at diagnosis was 6.17 years (0.33, 10.0). Sixteen (50%) cats were female spayed, 14 (43%) were male castrated; one cat each was female intact and male intact. Twenty-nine (91%) cats were domestic shorthair or domestic longhair; Tonkinese (n = 1) and Siamese-crosses (n = 2) were also represented. Body weight was available for 31/32 cats; median weight was 3.18 kg (1.90, 7.52). Seventy-five percent (24/32) of cats had received therapy prior to definitive diagnosis, including antibiotics (22/24), steroids (15/24) and antifungals (2/24); a variety of other supportive measures such as anti-emetics, appetite stimulants, gastroprotectants, non-steroidal anti-inflammatory drugs, hepatoprotectants and cardiac medications were also used.
Historical and clinical findings
The most common historical findings were weight loss (16/32, 50%), decreased appetite (13/32, 41%) and lethargy (12/32, 38%). The most common physical examination findings were tachypnea or dyspnea (15/32, 47%), increased respiratory sounds (14/32, 44%), fever (11/32, 34%), peripheral lymphadenomegaly (8/32, 25%) and ocular abnormalities (7/32, 22%), such as blindness, chorioretinitis and uveitis. Other pertinent findings included cutaneous masses or ulcerations (5/32, 16%), icterus (5/32, 16%), lameness (2/32, 6%), oral lesions (2/32, 6%), abdominal masses (2/32, 6%), abdominal distension (1/32, 3%) and splenomegaly (1/32, 3%).
Diagnostics
Hematologic (n = 31) and biochemical (n = 30) data collected within 10 days prior to or upon presentation to KSU-VHC are summarized in Table 1. Five of the 23 (22%) complete blood counts (CBCs) performed upon admission to KSU-VHC had decreased estimated platelet concentrations; all five of these cats also had pancytopenias. Platelet concentrations were difficult to assess for those CBCs provided by referring veterinarians because blood smears were not performed for all cats. Urinalysis was performed in 8/32 cats upon admission. The most common abnormality was proteinuria (88%, 7/8) ranging from trace to 3+ on urine dipstick; no urine protein-to-creatinine ratios were performed. Twenty-seven cats were screened for feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) by a commercial ELISA (Idexx); all tested cats were negative for both viruses.
Summary of hematologic and biochemical data for cats performed within 10 days of presentation. Parameters for complete blood counts (n = 23) and biochemistry panels (n = 21) performed at the KSU-VHC are expressed as a median and range. Data from bloodwork provided by referring veterinarians are included in counts and percentages of hematologic and biochemical abnormalities, but not in median and range calculations. Estimates of platelet concentrations are discussed within the body of the text
MCV = mean corpuscular volume, MCHC = mean corpuscular hemoglobin concentration, BUN = blood urea nitrogen, ALT = alanine aminotransferase, ALP = alkaline phosphatase
Thoracic and abdominal radiographs were performed in 24 and 7/32 cats, respectively. The most common thoracic radiographic finding was an interstitial pulmonary pattern (16/24, 67%). Five cats had a diffuse interstitial pattern, four had a miliary interstitial pattern, three had a nodular interstitial pattern and four had a mixed interstitial pattern. Hepatomegaly was identified in 6,26 (23%) cats based on thoracic (n = 4) or abdominal radiographs (n = 2) and splenomegaly was found in 3,7 (43%) cats on abdominal radiographs. Abdominal ultrasound was performed in 13 cats (41%). Seven of 13 (53%) cats had hepatomegaly or changes in hepatic shape or echogenic texture and 7/13 (53%) cats had splenomegaly or changes in splenic shape or echotexture. Five of 13 (38%) cats had changes in both the liver and the spleen. Other common findings included abdominal lymphadenomegaly (6/13, 46%), peritoneal effusion (5/13, 39%), and small or irregularly-shaped kidneys consistent with chronic kidney disease (5/13, 39%).
Definitive diagnosis of histoplasmosis was made by identification of fungal organisms in tissue by cytology (28/32), histopathology (2/32) or both (2/32). Necropsy was performed in two cats: one had Histoplasma organisms identified in the lungs, hilar lymph nodes, liver, spleen, bone marrow, kidney and heart; the other had Histoplasma species organisms identified only in the lungs. Multiple sites were sampled in seven live cats via aspirate and cytology unless otherwise noted. Histoplasma species organisms were identified in cutaneous masses on the head and leg of one cat, and in a peripheral lymph node and a duodenum biopsy of a second cat. Histoplasma species organisms were found in the liver and spleen of a third cat; in a peripheral lymph node and peripheral blood smear of a fourth cat; and in the endotracheal wash fluid and conjunctival biopsy of a fifth cat. An iridal mass and mammary mass were sampled in the sixth cat, but Histoplasma species organisms were only found in the mammary mass. The liver, spleen, adrenal gland and an abdominal lymph node were sampled in the seventh cat, but Histoplasma species organisms were only identified in the liver. A single site was sampled and Histoplasma species organisms identified in the remaining 23 cats. These sites included lung (n = 11), liver (n = 4), peripheral lymph node (n = 3), abdominal lymph node (n = 1), spleen (n = 1), bone marrow (n = 1), facial lesion (n = 1) and tongue (n = 1).
Initial therapy and outcome
Thirty of 32 cats underwent treatment for histoplasmosis. All 30 were treated initially with an azole antifungal drug with a median treatment time of 6 months (0.03, 22.0). Thirteen cats (43%) were treated initially with itraconazole with a median dose of 10.0 mg/kg/day (4.90, 20.0). Seventeen animals (57%) were treated initially with fluconazole with a median dose of 19.3 mg/kg/day (5.14, 33.0) divided into twice-daily administration. Thirteen of the 30 cats treated (43%) had been treated previously with steroids; six were in the itraconazole treatment group (6/13, 46%) and seven were in the fluconazole treatment group (7/17, 41%). Eleven of 30 cats (37%) were concurrently treated with steroids, either dexamethasone or prednisolone; however, in most cases, steroids were discontinued prior to completion of antifungal therapy. All 11 cats treated with adjunctive steroids were in the fluconazole treatment group and eight of these cats had significant respiratory clinical signs. Five cats (17%) were admitted to the hospital upon diagnosis for intensive management, which included, but was not limited to, intravenous fluid administration (n = 5), oxygen therapy (n = 3) and whole blood transfusion (n = 1). Four cats (13%) had an esophagostomy tube placed for nutritional support.
Outcomes for the 30 cats treated initially are summarized in Table 2. Six of the 30 cats died or were euthanased during initial therapy, including 3/13 (23%) treated with itraconazole and 3/17 (18%) treated with fluconazole. Three cats were still under treatment at the end of the study and one was lost to follow-up. Of those cats (n = 20) whose clinical signs resolved and therapy was discontinued, the initial therapy chosen was successful in 15/20 cats, while a treatment change (dose or drug adjustment) was required in 5/20 cats. These included 4/13 (31%) cats treated initially with itraconazole and 1/17 cats (6%) treated initially with fluconazole. One of the four cats treated initially with itraconazole was switched to fluconazole because of lack of response to therapy and a second cat was switched because of presumed adverse effects of itraconazole (liver enzyme elevation). A third cat developed immune-mediated polyarthritis suspected to be an adverse reaction to itraconazole, and itraconazole therapy was permanently discontinued without institution of an alternate antifungal therapy; clinical signs resolved in this cat and no recrudescence was reported. The fourth cat also experienced liver enzyme elevation; itraconazole was temporarily discontinued and then reinstituted at a lower dose. Clinical signs subsequently resolved and no recrudescence has been reported. The one cat treated initially with fluconazole that required a treatment change was switched to itraconazole because of a lack of response to fluconazole; this cat responded well to itraconazole and therapy was discontinued 10 months after diagnosis.
Outcome of cats following initial treatment with an azole antifungal drug
Those cats that died or required a treatment change during initial therapy were considered treatment failures. The median initial dose of itraconazole for the seven itraconazole treatment failures (three deceased, four treatment changes) was 10.0 mg/kg/day (9.00, 20.0). The median duration of treatment with itraconazole prior to treatment change or death was 2.0 months (1.0, 22). The median initial dose of fluconazole for the four fluconazole treatment failures (three deceased, one treatment change) was 17.4 mg/kg/day (7.57, 22.7) divided into two doses and the median duration of treatment prior to treatment change or death was 0.5 months (0.03, 4.0).
Recrudescence
Twenty cats in this study achieved clinical resolution of disease followed by discontinuation of antifungal therapy (Table 3). Eight of these 20 cats experienced recrudescence of clinical signs (Table 4). Of cats experiencing recrudescence, four had initially been treated with itraconazole (4/13, 32%) and four had been treated with fluconazole (4/17, 24%), which was not significantly different (P = 0.29). There was also no significant difference (P = 0.4) in the median disease-free interval for cats treated with itraconazole (41 months, 6, 74) and fluconazole (11 months, 4, 48).
Outcome of cats that achieved clinical resolution of histoplasmosis followed by discontinuation of antifungal therapy
Cat experienced recrudescence but was euthanased because of signs consistent with progression of long-standing chronic kidney disease. These signs did not appear to be associated with itraconazole treatment or a manifestation of histoplasmosis, although a necropsy was not performed
Specific clinical course for cats following recrudescence of histoplasmosis
Overall mortality
Of the 30 cats treated in this study, 10 cats (10/30, 33%) died or were euthanased because of complications associated with histoplasmosis, either during the initial episode of disease or subsequent recrudescence. There was no significant difference in mortality between those cats treated with itraconazole (5/13, 38%) and fluconazole (5/17, 29%) (P = 0.27). For cats that underwent treatment and for which follow-up information was available (n = 29), median survival time until death or the end of the study period was 19 months (4, 59). Sixteen cats were confirmed to be alive at the end of the study.
Owner survey
Owners of 29/32 cats participated in the follow-up survey. Results are summarized in Table 5. Owners reported their cats had exposure to multiple (20/29, 69%), a single (5/29, 17%) or none (4/29, 14%) of the potential sources of Histoplasma species spores included in the survey. Suburban (10/29, 34%) and rural (16/29, 55%) habitation were more common than urban (3/29, 10%) habitation in cats in this study.
Number and percentage of cats exposed to possible sources of Histoplasma spores based on owner survey (n = 29)
Eleven of 29 cats (38%) were considered to be strictly indoor animals by their owners. For these animals, the most common possible sources of exposure to Histoplasma species spores were potted plants (3/11, 27%), unfinished basements (4/11, 36%) or both (2/11, 18%). Owners of 2/11 (18%) cats that were housed strictly indoors did not report exposure to any of the possible sources discussed in the survey. The remaining 18 cats (60%) had some degree of outdoor access, from leash walks under supervision to living completely outdoors. For these animals, the most common possible sources of exposure to Histoplasma species spores were digging in outside soil (10/18, 56%), bats around the house (9/18, 50%), indoor potted plants (8/18, 44%) and unfinished basements (7/18, 39%).
Discussion
The results of this study support the use of fluconazole as an alternative to itraconazole in the treatment of histoplasmosis in cats at a dose of 20 mg/kg/day divided into twice-daily administration. Studies prior to the mid-1990s mainly reported the use of ketoconazole for treatment of feline histoplasmosis with disappointing survival rates (29–38%).2,3,6 A more recent study using itraconazole in eight cats with histoplasmosis reported a 100% survival rate, although five of these cats had previously received treatment with other antifungal drugs, which likely influenced these data. 5 Several case reports have also been published reporting the successful use of itraconazole for feline histoplasmosis.4,7 The overall survival rate reported in the current study (66%) is reflective of our clinical experience in treating this disease. This study is not powered to assess the effect of clinical signs and body system involvement on survival; however, in our experience, cats with severe respiratory involvement at presentation may have a higher mortality rate owing to death from respiratory arrest or euthanasia because of a poor prognosis perceived by the owner. With regard to clinical findings associated with feline histoplasmosis, the results of this study are generally consistent with those reported previously.1–6 The median age at presentation was 6.17 years, which is slightly older than cats in previous studies.2,3 Clinical signs and bloodwork abnormalities were consistent with previous studies.1–3,5
Prior to the study presented here, no studies comparing drugs used in the treatment of feline histoplasmosis have been published. Current recommendations regarding fluconazole are based largely on extrapolation from the human literature and the use of fluconazole is, thus far, rarely reported. 5 Therapeutic response leading to clinical resolution, recrudescence rates and mortality were not significantly different for cats treated with fluconazole and itraconazole (Tables 2 and 3), supporting the fact that feline histoplasmosis may be treated with fluconazole and the outcome can be expected to be similar to treatment with itraconazole.
In this study, 8/20 cats (40%) achieving clinical resolution and discontinuation of initial therapy experienced recrudescence of disease. The cause of recrudescence in these cases is unknown. Recrudescence may be associated with the type or duration of initial therapy, or may be reflective of the nature of the Histoplasma species organism with resolution of clinical signs reflecting a latent phase of infection and recrudescence reflecting reactivation. This calls into question appropriate therapy when recrudescence occurs. Drug resistance in feline histoplasmosis has not been reported, but could, theoretically, be involved in treatment failure. Additionally, target serum drug levels have yet to be established for azole antifungal therapy in feline histoplasmosis and may become important in therapeutic monitoring for both initial therapy and therapy during recrudescence. Finally, although the majority of cats treated today for histoplasmosis receive azole drugs as a first line of therapy, other antifungal drugs (eg, amphotericin B, terbinafine) may have a role in optimized treatment. Future studies are required to address these treatment issues.
The potential for adverse effects of medication are an important consideration when weighing therapeutic options. One study in rats demonstrated more severe biochemical (alanine aminotransferase and alanine phosphatase elevations) and histologic liver changes in rats treated with itraconazole when compared with those treated with fluconazole. 17 In the present study, the need for treatment adjustment was lower in those cats that received fluconazole initially (one cat) when compared with those that received itraconazole initially (four cats), which included three cats that required adjustment owing to presumed adverse effects of itraconazole.
Cost can be an important factor when choosing an antifungal medication, as cats in this study were treated for 6 months, on average. At our institution, a 1-month supply of itraconazole (Sporanox) for the average cat (5 kg cat, 10 mg/kg/day, receiving half of a 100 mg capsule daily) would cost $212.85. At this price, treatment may be cost-prohibitive for some clients. Compounding itraconazole is also a consideration which could reduce its price substantially but would carry potential concerns regarding stability, potency, purity, bioavailability and quality control; significant pharmacokinetic differences have been identified between commercial and compounded itraconazole in another species.18,19 Alternatively, at our institution, treatment with fluconazole (generic formulation) for the same size cat (5 kg, 20 mg/kg/day, receiving one 50 mg tablet q12h) for 1 month would cost $18.60.
Histoplasmosis is traditionally considered to be a disease of outdoor cats; however, this assumption has recently been questioned in the literature. In 2004, Johnson et al published a case report of two cats with histoplasmosis in the San Joaquin Valley in California, an atypical location for histoplasmosis to be diagnosed. Not only was the geographic distribution considered to be atypical, but both cats were kept strictly indoors. 4 In the present study, 38% of affected cats were reported to be housed strictly indoors — a much higher proportion than would be predicted by the traditional dogma. These results suggest that a substantial proportion of cats with histoplasmosis are exposed to Histoplasma species microconidia by routes other than direct outdoor exposure to soil. Other possible sources of exposure commonly reported by owners include potting soil in indoor plants and unfinished basements. Further investigation, including soil examination and comparison with the general feline population, is warranted.
There are several limitations to the study presented here. Analysis of response to therapy leading to clinical resolution of disease, mortality and recrudescence rates did not demonstrate a significant difference between cats treated with itraconazole and fluconazole. However, because of the limited sample size, this study may lack the statistical power to demonstrate such a difference. Additionally, treatment choice was not randomized but rather was at the discretion of the clinician. Interestingly, all cases of feline histoplasmosis in this study treated with itraconazole were diagnosed prior to 2007 and those treated with fluconazole were diagnosed in 2007 or later. Drug choice may have been based on drug cost at the time of diagnosis, as fluconazole went off patent in 2004 and a less expensive, generic formulation became available at the KSU-VHC dispensary in 2005. Therefore, the outcome of the comparison of cats treated with these two drugs may be biased by the time at which the cats were diagnosed and treated. Alternatively, drug choice may be reflective of clinician preference, which could also be a source of bias. The severity of disease and use of steroids at, or prior to, initiation of antifungal therapy may be additional confounding elements when comparing itraconazole and fluconazole.
The retrospective nature of this study and the lack of case controls precluded statistical evaluation of risk factors for histoplasmosis. The data obtained from the owner survey and follow-up must be interpreted with caution because this information may be skewed by owner interpretation. Additionally, the cases presented here represent only the hospital population of the KSU-VHC which provides a service to a wide geographic area, including Kansas, Nebraska, Iowa, Oklahoma and Missouri. These cases may not be representative of the national or global population affected by feline histoplasmosis. Finally, the sample size was limited and the clinical course, treatment and outcome of the cases presented here were heterogeneous. Given these factors, the results should be interpreted with caution, as the majority of information is descriptive. Prospective controlled trials are necessary to support the findings presented here.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors
Conflict of interest
The authors do not have any potential conflicts of interest to declare.