Feline Histoplasmosis: A Retrospective Study of 22 Cases (1986–2009)

Introduction

Histoplasmosis is a systemic fungal infection caused by the dimorphic fungus Histoplasma capsulatum, which primarily affects the mononuclear macrophage system.^1,2 It is the second most common fungal disease reported in cats after cryptococcosis.³ Different forms of histoplasmosis (e.g., pulmonary, disseminated, primary gastrointestinal [GI]) have been reported in cats.^4,5 Disseminated disease is considered a form of infection that occurs when there is involvement of at least one organ system outside the limits of the thoracic cavity. Most cats reported in the literature have the disseminated form of the disease.³ Clinical presentations are reported to be nonspecific and include weight loss, lymphadenopathy, lethargy, fever, and respiratory signs including dyspnea, tachypnea, nasal discharge, and coughing.^6,7 Other clinical manifestations in few case reports include cutaneous nodules, ocular disease, diarrhea, and lameness.⁸ Either a normocytic or microcytic, normochromic, nonregenerative anemia and hypoalbuminemia are common laboratory abnormalities observed in feline histoplasmosis.^9–13 Thoracic radiographic patterns in cats with histoplasmosis have been described as fine, diffuse miliary, or nodular-interstitial and alveolar infiltrates.¹⁴ In most cases of histoplasmosis, diagnosis has been established by cytologic or histopathologic preparations with Diff-Quick, Wright-Giemsa, and modified Wright stains.^11,15,16 Serology has not been shown to be clinically useful in the diagnosis of feline histoplasmosis.^7,9 Ketoconazole, itraconazole, and fluconazole, either alone or in combination with amphotericin B, have been successfully used to treat histoplasmosis in cats.^7,11 Combination antifungal therapy may be more efficacious than single agent therapy.^2,17,18 Itraconazole is reported to have fewer side effects and appears to be more effective than ketoconazole.^2,10 Histoplasmosis in cats has been associated with low morbidity, but high mortality rates.^1,13

To the authors’ knowledge, the published literature on feline histoplasmosis includes only case reports and four retrospective studies.^1,9,13,14 The objective of this study was to describe the clinical findings, diagnosis, treatment, and outcome of cats with histoplasmosis presented to the Virginia-Maryland Regional College of Veterinary Medicine Teaching Hospital.

Materials and Methods

Cases with a diagnosis of histoplasmosis were identified from cats examined at the Virginia-Maryland Regional College of Veterinary Medicine Teaching Hospital between1986 and 2009 via an electronic search of medical records for “histoplasmosis” that was restricted to the feline population. Inclusion criteria for cats in this study were the identification of Histoplasma organisms on cytologic and/or histopathologic specimens (Table 1). Twenty-two cases met the criteria for case selection. Data collected included signalment, body weight, clinical signs, physical exam findings, complete blood count (CBC), serum biochemistry profile, urinalysis (UA), radiographic and ultrasonographic findings, cytology, necropsy and histopathology findings, specific treatment(s), and treatment duration. There were two different sets of reference ranges for CBC and serum chemistry based on the laboratory used. These two sets of reference ranges were combined, and the lowest or highest values (as appropriate) of the combined reference ranges were used as the cutoff.

TABLE 1 Methods Used to Diagnose Histoplasmosis in 22 Cats

*

One cat had negative histopathology on endoscopic samples, but was positive on necropsy.

†

Some cases had more than one organ/tissue cytology performed.

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Cats were classified into one of the three following categories: disseminated, pulmonary, or GI. Cats were included in the disseminated disease group if the organism was identified in at least one organ system based on cytology and/or histopathology. Cats were included in the pulmonary disease group if the cat had clinical signs and radiographic findings of pulmonary disease and Histoplasma organisms were limited to the respiratory system only. Cats were included in the GI group if the clinical signs were associated with the GI system (e.g., vomiting, diarrhea, weight loss, anorexia) and the biopsy obtained via endoscopy or cytology obtained by rectal smear revealed the presence of Histoplasma organisms.

Treatment was attempted in 15/22 cats with antifungal agents, but duration of treatment was available for only 14/15 cats, and the dose for drug therapy was available for only 11/15 cats. Cats were classified as survivors if they were alive at the time of discharge from the hospital and were classified as nonsurvivors if they died or were euthanized before discharge. Follow-up was achieved by either evaluating the medical records or telephone contact with either the referring veterinarians or the cat owners.

Results

Histoplasmosis was diagnosed in 22 of a total of approximately 11,400 cats during the study period (1986–2009), equivalent to ∼0.2% of the total feline hospital population. Of these, 17/22 (77%) were domestic shorthair, 16 were female (13 spayed), and 5 were male (3 neutered). In one case, the sex was not recorded. Thirteen of the 22 cats had no travel history outside Virginia, and the travel history was not available for 6 cats. Of the remaining three cats, travel histories included trips to Rhode Island, North Carolina, and Pennsylvania. Median and mean±standard deviation age at presentation were 9 yr (range, 0.4–19 yrs) and 8.8±5.3 yr, respectively. Median body weight at presentation was 3.36 kg (range, 1.27–7.77 kg). Physical exam findings were available for 20/22 cats. The CBC, serum biochemistry, and UA were available in 14/22 (64%), 12/22 (55%), and 10/22 (45%) of the cases, respectively. Thoracic radiographs were available for 15/22 cats (68%). Cytology, necropsy, and histopathology were performed in 18/22 (82%), 11/22 (50%), and 14/22 (64%) of the cats, respectively (Table 1). Eight of the 22 cats had both cytology and histopathology performed.

The most common presenting complaints recorded in the medical records of the 22 cats were weakness (68%), weight loss (50%), and anorexia (45%). Clinical signs related to respiratory system were present in 9/20 cats (45%). Respiratory signs observed in these nine cats included dyspnea (44%), tachypnea (33%), nasal discharge (11%), and coughing (11%). In three of nine cats (33%), respiration was recorded to be abnormal, but no specific pattern was described. Some cats had more than one respiratory sign. Less frequent presenting complaints in the 22 cats included vomiting and diarrhea (14%), blindness (4.5%), and lameness (27%). Lymphadenopathy was reported in 11/20 cats (55%). Of those 11 cats, peripheral lymph nodes were enlarged in 6 (55%), mediastinal lymph nodes in 2 (18%), mesenteric lymph nodes in 4 (36%), and both peripheral and mediastinal lymph nodes in 1 (9%). In 4/20 cats (20%), lameness was noted on physical exam. Ocular exam findings were recorded in 20/22 cats (91%), and retinal detachment was present in 5/20 (25%) cats.

CBC results revealed that 6/14 cats (43%) were anemic, with a median hematocrit of 14.8% (range, 10.6–21.6%; reference range, 29–47%). In four of six cats (67%), the anemia was classified as nonregenerative and normocytic. Only 1/14 cats with anemia had a leukocytosis (leukocyte count was 51×10³/μL; reference range, 5.5–14.5×10³/μL). Two cats had thrombocytopenia (range, 18.9–291×10³; reference range, 300–800×10³). Pancytopenia was reported in one cat, but no feline leukemia virus (FeLV) test result was available for this patient. Serum biochemistry profiles revealed hypoalbuminemia in 9/12 cats (75%), with a median value of 2.5 g/dL (range, 1.8–2.8 g/dL; reference range, 2.9–4.0 g/dL). Hypocalcemia was observed in 5/12 cats (42%), with a median value of 8.2 mg/dL (range, 7.8–8.5 mg/dL; reference range, 8.7–10.5 mg/dL). Ionized calcium was not measured in any of those cases. All cats with hypocalcemia had concurrent hypoalbuminemia. UA was within normal limits in all 10 cases that had results recorded in the medical record. FeLV and feline immunodeficiency virus testing was conducted in 18/22 cats (82%). Five (28%) were positive for FeLV, and four of those five cats were FeLV positive on the immunofluorescence assay at the time histoplasmosis was diagnosed. Examination of the buffy coat was performed in only 2/22 cats and was positive in 1 cat. Serological testing for the H. capsulatum titer was performed in only one cat and was negative.

Thoracic radiographic patterns included interstitial (diffuse or nodular) in 6/15 cats (40%), miliary in 1/15 cats (6%), and mixed (interstitial, bronchial, and alveolar) in 2/15 cats (13%). In 6/15 cats (40%), thoracic radiographic findings were within normal limits. Of the nine cats that presented with abnormal respiratory signs, eight had thoracic radiographs performed. Seven of those eight cats had abnormal thoracic radiographic findings, and the radiographs for the remaining cat were lost; however, Histoplasma organisms were observed in lung macrophages on necropsy of that cat. Abdominal ultrasonographic findings were available for 14/22 cats (64%). Lymphadenomegaly (peripheral and/or mesenteric), occasional renomegaly, and adrenomegaly were reported.

The disseminated form of the disease was diagnosed in 15/22 cats (68%), and GI histoplasmosis was diagnosed in 3/22 cats (14%). Histoplasma organisms were present on histopathologic examination of the gastroduodenal biopsies in two cats and cytology of rectal mucosa in one cat. Those three cats had no clinical respiratory signs, and their thoracic radiographs were normal. The pulmonary form of the diseases was present in 4/22 cats (18%).

In this study, 7/22 cats were euthanized or died without treatment. Thirteen cats were administered a single antifungal agent (itraconazole or ketoconazole), and two cats were prescribed a combination of itraconazole and amphotericin B (Table 2). One of the two cats prescribed the combination therapy was switched from itraconazole to fluconazole after 37 days of treatment (4.4 mg/kg per os [PO] q 12 hr for 2 mo). The dose of itraconazole prescribed to cats in this study varied from 4 mg/kg PO q 12 hr to 16 mg/kg PO q 24 hr. Itraconazole was administered q 12 hr in six cats and q 24 hr in three cats. One cat was started at 16 mg/kg q 12 hr but the dose and the frequency of administration were later decreased to 8 mg/kg q 24 hr. The frequency of administration was unknown in three cats. The remaining two cats were treated with ketoconazole. The dose was only available for one cat (10 mg/kg PO q 12 hr). Amphotericin B was prescribed to 2/15 cats (Table 2). Both of those cats underwent diuresis during amphotericin B treatment. The median dose of itraconazole in cats that survived to discharge and did not have any change in dose during therapy was 10 mg/kg/day (Table 2).

TABLE 2 Treatment and Outcomes of 12 Cats Diagnosed with Histoplasmosis that Survived to Discharge

AMA, abdominal mucinous adenocarcinoma; HCM, hypertrophic cardiomyopathy; NA, not available; PO, per os.

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The duration of treatment was available for 14/15 cats (93%). The median duration of treatment in those 14 cats was 3.6 mo (range, 0.06–6 mo). The short duration of treatment indicates that patients ultimately died or were euthanized prior to completing the course of therapy. The median duration of antifungal treatment in cats that survived to discharge was 5 mo.

As summarized in Table 2, 12/22 cats (55%) survived to discharge. Seven died or were euthanized without treatment, and three cats died during the initial treatment period (within 1–7 days). Four of the cats that survived to discharge were eventually lost to follow-up. Two cats died at 100.5 and 30.3 mo for reasons unrelated to histoplasmosis (one died due to hypertrophic cardiomyopathy and the other due to abdominal mucinous adenocarcinoma, respectively) The overall median survival time was 28.9 mo (range, 0.57–100.5 mo). Seven untreated cats died or were euthanized within 1–16 days of presentation. Antifungal therapy was attempted in four of the five FeLV-positive cats. Three of those cats were lost to follow-up, and the fourth cat died 2 days after initiating treatment. The FeLV-positive cat that was not treated died the same day of diagnosis. Among the FeLV-positive cats with histoplasmosis, three of five (60%) were categorized as survivors. The FeLV test was negative in 13/18 (72%) cats, and survival to discharge in those cats was 54% (7/13).

Discussion

Feline histoplasmosis is an uncommon disease of cats. In this study disseminated histoplasmosis was the more common form of the disease, followed by the pulmonary and GI forms. Organ involvement at the time of diagnosis in the disseminated form included lungs, lymph nodes, liver, spleen, kidney, adrenal glands, eyes, bone marrow, and the GI tract. The GI form was rare. Organisms were found in the gastroduodenal and rectal mucosa on histopathology and cytology, respectively. In previous studies, histoplasmosis was more common in young cats, with no breed or sex predilection. In this study middle-aged, female domestic shorthairs were more commonly affected.³ In this study cats affected with histoplasmosis were older (mean age was 8.8 yrs) than previously reported (mean age of 3.9 yrs).³

Cats affected with histoplasmosis may present with signs of anemia, lethargy, weight loss, fever, and anorexia. These clinical findings were common in this study. In addition, 20/22 cats (91%) had ocular exams performed, and 5/20 (25%) had retinal detachment. This finding was different from one previous report in which 100% of cats had retinal detachment with histoplasmosis (but in that study ocular exams were only performed in 4/20 cats).⁹ In the current study a normocytic, nonregenerative anemia was present in most of the anemic patients (4/6), with only a rare occurrence of pancytopenia. Other studies report a moderate to severe normocytic or microcytic, normochromic, nonregenerative anemia with or without pancytopenia.^8,12,13 Hypoalbuminemia and hypocalcemia were the most common biochemical abnormalities noted in the current study, and all hypocalcemic cats were also hypoalbuminemic. Hypoalbuminemia was detected in 9/12 cats (75%) and was considered mild to moderate. These findings were attributed to either decreased albumin synthesis or loss of protein from the GI tract rather than renal loss (due to the absence of proteinuria in those cats).

Hypocalcemia is a different finding from reports in the literature.^2,19,20 It is likely due to low albumin concentration and a decrease in the protein-bound fraction of calcium. Because ionized calcium was not measured in any of cats in the current study, the presence of a true hypocalcemia cannot be concluded. UA was performed in 10/22 cats (45%) and was normal in all cases, which is a similar finding to previous studies.^20,21

Examination of a buffy coat preparation may enhance diagnosis through the detection of circulating infected cells.^12,15 In the current study a buffy coat preparation was examined in 2/22 cats (9%) and was diagnostic for histoplasmosis in 1 cat. Serology for H. capsulatum was performed in only one cat in this study and was negative. Nested polymerase chain reaction (PCR) has been used to detect H. capsulatum in paraffin-embedded skin samples in dogs in Japan.²² To the authors’ knowledge no such study has been reported regarding the use of this PCR test in cats. H. capsulatum antigen detection in urine, serum, bronchoalveolar lavage fluid, and cerebrospinal fluid can be used during the active infection phase when antigens enter body fluids. Antigen is found in the urine of 80–95% cases of progressive disseminated histoplasmosis in humans.²³ Neither PCR nor antigen detection was used as diagnostic tools for cats in this retrospective study. Fine-needle aspirate of tissues or suspected lesions was one of the least expensive methods for diagnosing histoplasmosis in the current study.

Thoracic radiographs were normal in 6/15 cats (40%). An interstitial pattern was the most common radiographic pattern in six of nine cats (67%) in the current study. Similar findings have been reported in a retrospective study of 18 cats with pulmonary histoplasmosis and in a review of 37 cases of pulmonary histoplasmosis in dogs and cats.^14,24 The appearance of alveolar infiltrates has also been considered to indicate a grave prognosis.²⁴ A mixed alveolar and bronchial pattern was observed in 2/15 cats included in the current study. Of those two cats, one was euthanized 1 day after presentation because of worsening clinical signs, and the other cat was alive 50 mo after diagnosis.

This study revealed a high infection rate (28%) of FeLV in cats with the disseminated form of histoplasmosis. This incidence is almost three times higher than previous reports (range, 8–11%).^9,13 In the current study, four of five FeLV-positive cats (80%) were viremic based on a positive immunofluorescence assay. The higher incidence of histoplasmosis in the cats included in this retrospective study may be attributable to suppressed immune response due to FeLV that allowed the opportunistic organism (H. capsulatum) to grow. However, based on results of this study, the coinfection of FeLV with histoplasmosis did not appear to worsen the survival to discharge rate in cats.

In 11/15 cats (73%) included in this study, itraconazole was used as a single agent antifungal therapy. This antifungal agent was the treatment of choice in feline histoplasmosis, as has been reported in previous studies.^10,25 Based on this study, it is difficult to generalize the effects of ketoconazole or combination therapy for treatment of feline histoplasmosis because of the limited number of cats treated with these regimens. Disseminated disease in cats has been associated with low morbidity and high mortality rates.¹ The survival to discharge in this study was 55% (12/22). In the majority of studies of feline histoplasmosis, treatment was not attempted, and the survival time constituting a successful treatment was not defined. Clinkenbeard et al. (1987) reported a maximum remission time of 37 mo in a cat treated with ketoconazole.¹³ In the current study the maximum survival time in one cat was 100.5 mo and another cat is still alive (at 70 mo) without recurrence of clinical signs.

Conclusion

To the authors’ knowledge this study reports the largest number of feline cases of histoplasmosis and the largest number of cats in which treatment was attempted. Feline histoplasmosis predominantly affected middle-aged female domestic shorthairs, and the disseminated form of the disease was the most common manifestation. Three of four cats with FeLV infection that received treatment were lost to follow-up; therefore, the effect of FeLV on response to treatment could not be determined. Although the current study has the largest number of cases compared with any previous study, the numbers were still limited.