Systemic Fungal Infections
Ferrets are susceptible to systemic infections caused by the fungi Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Cryptococcus gattii, and Histoplasma capsulatum. Also Pneumocystis carinii, previously considered a protozoa, has been classified as a fungus and causes pneumonia in immunosuppressed ferrets.
Blastomycosis
This disease has been reported in a ferret; the case had many of the same characteristics of the disease in dogs [1]. North American blastomycosis is a systemic fungal disease caused by B. dermatitidis, and infects primarily humans and dogs [2,3]. The disease has also been reported in horses, cats, and sea lions. The fungus is dimorphic, and grows as a yeast in tissue and in enriched culture media at 37°C and as a mold at room temperature.
Epizootiology and Control
The disease occurs in both domestic animals and humans. The reservoir is probably soil and decaying wood. The mode of transmission is most likely by inhalation of the conidia in spore-laden dust. While most cases are sporadic, outbreaks of the disease in humans have been recorded [4]. The disease does not appear to be transmitted directly from animal to animal or from animal to human. This disease has a global distribution and occurs most frequently in central and southeastern United States, Canada, Africa, and (rarely) in Latin America [3]. The low number of reported cases in humans and animals (including the ferret) suggests that mammalian hosts are relatively resistant to the disease. Animals housed outdoors with exposure to fungus-laden dust may be at a higher risk of infection.
Clinical Signs and Pathology
Systemic blastomycosis is most often a chronic granulomatous mycosis, primarily affecting the lungs. Cutaneous blastomycosis is also diagnosed and characterized by chronic ulcerated skin lesions, which spread slowly and peripherally. In the affected ferret, an ulcerated swelling on the metacarpal pad was noted [1]. Tissue imprint of the lesion demonstrated broad-based budding yeasts consistent with B. dermatitidis. The animal sneezed and coughed, and an enlarged spleen was palpated. Thoracic radiography revealed reticulonodular interstitial pattern consistent with pneumonia, with focal consolidation of a portion of the lung, and pleural fluid. These findings were consistent with mycosis or neoplasia. Necropsy revealed bilateral diffuse granulomatous pneumonia characterized by nodules throughout the lungs. Granulomatous pleuritis, meningoencephalitis, and splenitis were also noted [1].
The disease described in the ferret represents the chronic respiratory form, with spread of the disease to other organs by way of blood or lymph [1].
Diagnosis
Isolation of B. dermatitidis from cutaneous or lung aspirate confirms a diagnosis of the disease. Tissue imprints demonstrating the budding yeast provide a tentative diagnosis. The characteristic “snowstorm” interstitial changes seen in cases of canine blastomycosis are also present in the ferret [1,5]. Agar immunodiffusion demonstrating circulating antibody titer to the organism may be useful in establishing a clinical diagnosis of the disease.
Treatment
The treatment used in canines consists of amphotericin B (AMB) at dosages of 0.25–1 mg/kg given intravenously for several treatments, until a total dosage of 0.7–25 mg/kg has been administered [2,6,7]. Treatment with ketoconazole (10–30 mg/kg) orally once daily for 60 days has also been used successfully in dogs [8]. Standard treatment recommended now consists of itraconazole (ITZ) given orally. For those dogs that can't absorb ITZ, AMB can be used. Amphotericin lipid complex can be substituted, in that it is less nephrotoxic. Relapses have occurred in 20–25% of dogs receiving antifungal drugs [2].
Initial treatment in the ferret with AMB intravenously (0.5 mg in 1 mL 5% dextrose) every other day for a calculated dosage of 0.8 mg /kg AMB was instituted, supplemented with 5 mg of oral ketoconazole. Blood urea nitrogen (BUN) levels were monitored, and fluid was given subcutaneously as needed. Because the first treatment of AMB caused anorexia, pyrexia, and azotemia, the dosage was reduced to 0.25 mg (0.4 mg/kg) to be given intravenously as often as BUN level values permitted; this regime was established according to the clinical appearance of the animal, and was instituted approximately 1 week after the first treatment. The animal responded by resolution of the ulcer in the forepad and regression of primary lesions. Because of inaccessible veins, intravenous AMB had to be discontinued, and subcutaneous AMB was given every other day. Two weeks after initiation of subcutaneous treatment, however, the ferret relapsed and was euthanized.
Blastomycosis treatment in ferrets obviously requires further study. Jugular catheterization may aid in effective treatment with amphotericin, monitoring of BUN values, and provision of fluid therapy; intraperitoneal injections may also be attempted [1]. Increasing the oral dose of ketoconazole to 30 mg/kg/day in the ferret may increase its efficacy in treating blastomycosis.
Recently, the Food and Drug Administration (FDA) has taken several actions regarding the use of oral tablets of ketoconazole. This includes limiting the use of the drug, warning that oral ketoconazole can cause severe liver and adrenal gland damage, as well as potential harmful drug interactions with other medications. They recommend that the drug should not be a first-line treatment for fungal infections. The FDA has also approved a new patient Medication Guide containing information on the potential risks associated with oral ketoconazole
Coccidioidomycosis
Coccidioides immitis is a fungal organism found in the soil of particular geographic locales. The regions where C. immitis grows have sandy, alkaline soils, high environmental temperatures, and low elevations. Growth of the fungus in the soil produces mycelia which form square to rectangular arthrospores. It is these spores that are detached, become aerosolized, and are subsequently inhaled or, infrequently, contaminate existing wounds.
Epidemiology and Control
In the United States, the disease is given the name San Joaquin Valley Fever, a reference to where it was endemic in California. Cases are also observed in southwestern parts of the United States, particularly Arizona and southwest Texas. In 2011, coccidioidomycosis was the second most commonly reported nationally notifiable condition in Arizona and the fourth most commonly reported in California [9,10]. The disease has been described in all species of domestic animals, including ferrets where it has been reported in three animals [11].
Clinical Signs and Pathology
Three cases of coccidioidomycosis were reported in ferrets residing in the Southwestern United States [11]. In the first case, the male ferret was 1.5 years old. It presented with weight loss and lethargy of 3 weeks duration and had been coughing for 3 days. The animal had lost 36% of its weight during the preceding 6 months. The ferret had moderate pharyngeal hyperemia, but its hemogram was normal, as was its temperature. Tetracycline (25 mg) per os 3 times daily was prescribed for a 7-day period. Two weeks after therapy, the coughing had progressed, and the submandibular lymph nodes were enlarged and tender. Radiographs revealed an increased interstitial pattern in the cranial lung lobes. Coccidioidomycosis precipitation and CF tests were negative, and the ferret was given amoxicillin 12.5 mg BID per os for 10 days. The ferret was reexamined and prescribed prednisolone once daily for 16 days. Approximately 10 weeks later amoxicillin was again prescribed for the cough which had not abated. One year later, the animal was lethargic, weak, and had continued to lose weight. An abdominal mass was palpated, lameness of the right front leg was noted, and melena was also observed. Tetracycline was again dispensed; radiographs and a CBC were performed. The ferret was referred to the author's clinic 3 weeks later [11]. Radiographs revealed circular radiodensities at the hilar region of the lung but no abnormalities were seen on radiographs of the right leg. The CBC reflected a stress leukogram with a WBC of 24,900. A coccidioidomycosis screen was precipitant CF positive. A presumptive diagnosis of coccidioidomycosis was made, and the animal was placed on 10-mg ketoconozole BID. However, no clinical improvement was noted, and the animal was euthanatized 6 weeks later.
A 7-month-old female ferret (case #2) raised in the eastern United States was purchased at a local pet store in the Southwest [11]. The ferret appeared healthy until 2 days prior to presentation when it was noted to be anorexic and lethargic. Radiographs revealed two circular radiodense areas in the mediastinum and caudal right lung lobe. The animal died under anesthesia while the clinician attempted a tracheal wash.
The third ferret (case #3) presented as thin and dehydrated to a local clinic [11]. A mucoid nasal discharge and a draining wound in the left stifle were noted. The ferret was administered 2-mg gentamycin, and the owners were instructed to administer amoxicillin per os for 7 days along with oral B complex preparation and to clean the leg wound with hydrogen peroxide. The ferret, examined again 3.5 weeks later, had a swollen draining tract in the left tibiotarsal area. A smear of the draining fluid revealed neutrophils and bacteria. Gentamycin was given for 4 days without improvement. Amikacin sulfate at 3 mg/lb twice daily subcutaneously was begun. Improvement was noted and the dosage changed to 6 mg/lb every 24 hours. The animal initially responded, but 5 weeks later, the area was again swollen and draining. Radiographs showed radiodensity of the right radius. The animal was euthanatized 2 days later after the animal failed to respond to gentamycin and subcutaneous fluids.
Unfortunately, a necropsy was not performed on case #1. A necropsy on the second ferret disclosed granulomatous lesions with endosporulating spherules in the lung and those lymph nodes which had been examined. The lesions and organism were compatible with Coccidioides immitis infection. Gross examination of case #3 indicated that the draining tract appeared to be restricted to muscle and soft tissue of the right corpus and right and left tarsus. Coccidioides sp. was isolated from the right tarsal area, and endosporulated spherules were observed microscopically in the spleen. Histological lesions of the lung and bone were not described [11].
In humans and dogs, the inhaled arthrospores can produce respiratory signs in 1–3 weeks [12]. A neutrophilic response is noted, followed by mononuclear cell infiltration. Cell-mediated immunity is an important host defense to eliminate the organism. Disseminated disease also occurs in dogs and humans. The organs affected, once the disease has spread from the respiratory system, include bone and joints, abdominal organs, heart, testicles and CNS. Systemic signs are dependent on organ involvement [13].
Diagnosis
Radiographs of the thorax can be helpful. A diffuse interstitial pattern is often noted. Mediastinal lymphadenopathy can be seen. Radiographic findings can also be consistent with osteomyelitis [14]. Confirmation is based on identification of the organism in cytology or biopsy. Special stains such as silver stains or periodic acid–Schiff (PAS) are used for visualization of the fungi. Because the mycelial phase of fungal growth is highly infectious, veterinary hospitals not equipped with biocontainment hoods should not attempt to culture this organism. Indeed, diagnosis usually relies on histological or cytological diagnosis. Serological tests such as CF are sometimes used for diagnosis.
Treatment
Long-term antifungal therapy for respiratory or disseminated disease is prescribed. Ketoconazole therapy has been used to treat the disease in dogs and less frequently in cats. Fortunately, the drug can be administered orally. For dogs, the oral dose is 5–10 mg/kg every 8–12 hours for 6–12 months. However, recently the FDA has warned that oral ketoconazole in humans can cause deleterious hepatotoxic effects on liver and adrenal gland insufficiency. They also caution that oral form of the drug can lead to harmful drug interactions with other medications. The FDA has also approved a new patient Medication Guide containing information on the potential risks associated with oral ketoconazole. Amphotericin given intravenously is an alternative drug given to dogs and still is the drug of choice in treating the disease in humans. If the eye is the only site of disease and it does not respond to fungal treatment, enucleation is sometimes curative [15]. In ferrets with the disease, oral ketoconazole was instituted in one animal at a dose of 10 mg/kg BID for a period of 6 weeks [11]. Unfortunately, it did not respond to this treatment.
Prognosis
Localized infection in humans has a favorable prognosis even without treatment. However, it is recommended that dogs with localized infection be treated because of the guarded prognosis for dogs with disseminated coccidioidomycosis. Not enough clinical data are available in ferrets to ascribe a clinical prognosis.
Cryptococcosis
The genus Cryptococcus is composed of many species. Cryptococcus neoformans is considered the primary human pathogen [16].Several cases of cryptococcosis have been described in the ferret. The disease is caused by C. neoformans or Cryptococcus gattii. C. neoformans is subdivided into C. neoformans var. neoformans and C. neoformans var. grubii. C. gattii was formally classified as C. neoformans var. gattii [17,18]. Cryptococcus spp. are dimorphic basidiomycetous fungi. The life cycle involves vegetative growth as budding yeast, with the ability to transition to a filamentous form. Cryptococcal strains are now divided into eight molecular types instead of using serotypes [19]. The disease can present clinically as a subacute or chronic meningoencephalitis, but in the ferret, involvement of other organs is commonly reported. Ferrets have a spectrum of signs, including respiratory, cardiac, abdominal, CNS, and skin manifestations [19].
Epizootiology and Control
The organism is present universally and often found in the soil. C. neoformans growth is enhanced by creatinine, which is found in the excreta of pigeons and certain other birds. It is probable that one ferret used to control rodents in an aviary was infected from pigeon excreta present in the environment [16]. Control therefore includes minimizing contact with soil contaminated with the feces of pigeons and other birds. C. gattii is associated with decaying plant matter found in depressions of certain types of trees, particularly eucalyptus. It is most commonly cultured in tropical and subtropical areas [20]. This organism has been recently associated with disease in humans and animals residing in the Pacific Northwest of North America [17]. Susceptibility to the disease is increased during corticosteroid therapy or when the animal is otherwise immunosuppressed. Cryptococcal infections have been reported in ferrets residing in the United States, Canada, Spain, Australia, and the United Kingdom.
Clinical Signs
Ferrets diagnosed with crytococcus have been increasingly reported in the literature. In the first reported case, a mature albino male ferret (case #1) was found dead by its owner in England [21]. No clinical signs prior to its death had been noted.
Cryptococcosis was also diagnosed at necropsy in a 3-year-old male (case #2) suffering from cardiomyopathy [22]. The animal was examined because of posterior paralysis and listlessness. Neurologic examination revealed hyperaphia of L2 and L3 and decreased sensation and slow withdrawal of the hind limbs [22]. A diagnosis of intervertebral disc disease was made; the ferret was treated with dexamethasone for 1 month. The ferret's condition improved markedly for 1 month, but it was examined at another veterinary clinic because of serous nasal discharge and moderate dyspnea. Therapy with antibiotics was instituted for 5 days, but the animal's condition worsened and it became anorectic. Cardiomegaly and pulmonary edema were diagnosed by thoracic radiography and electrocardiography. Furosemide (1 mg/kg), cephalexin (10 mg/kg), digitalis (0.0025 mg/kg), and oxygen were administered, but the animal died the following day.
In case #3, reported from Australia, a 3-year-old ferret was purchased by an aviary owner to control wild mice [23]. Pigeons were commonly attracted to the aviary. Initially, the ferret appeared to work effectively as a “mouser,” but after several weeks the mouse population again increased. The ferret was given to a ferreter, who noticed that the animal had a nasal discharge and was inactive; it died 3 weeks later.
In case #4, a ferret with small, noncleaved lymphoma had cryptococcal yeasts observed in the cervical lymph node [24].
In case #5, an 18-month-old castrated male, adopted from a shelter 2 months previously was presented to a veterinary hospital with a history of regurgitation. On physical examination, there was a notable enlargement of the right submandibular lymph node.
In case #6, a 5-year-old castrated male (body weight 1.2 kg) residing in Australia, presented with subcutaneous swelling on the nasal bridge immediately caudal to the nasal plane. The ferret at presentation was lethargic, coughing, and sneezing. The mass was removed surgically and submitted for histology and culture [25]. This ferret's sibling (case #7), developed abscessation of the retropharyngeal lymph node 12 months later. Cryptococcal microsatellite DNA analysis indicated that the cryptococcal organisms from the two ferrets were indistinguishable [26]. Although the ferret improved on itraconazole therapy (33 mg PO daily), the owners elected to euthanize the ferret because of a worsening skin condition [26].
In case #8, a 4-year-old, castrated male ferret living in Massachusetts and housed indoors, lost weight over a 15-month period and presented with retching, diarrhea, and lethargy of 2-day duration [27]. The animal was lymphopenic, and had hypocalcemia, hypoalbuminemia, and hyperglobulinemia. Radiography revealed a pulmonary bronchointerstitial pattern, and an abdominal ultrasound indicated that the ferret had a pancreatic mass and mesenteric lymphadenopathy. After 2 weeks of treatment to stabilize clinical signs, histologic examination of a mesenteric lymph node biopsy taken during exploratory laparotomy demonstrated cryptococcal organisms. The ferret died 2 days after itraconazole (PO) and amphotericin B (IV) was administered.
In case #9, an 18-month-old ferret with bilateral mandibular lymphadenopathy, presented with acute onset blindness diagnosed by ophthalmological examination as being caused by bilateral exudative chorioretinitis. Biopsy and histology of the mandibular lymph node indicated the presence of encapsulated yeast organisms. The organisms were confirmed to be C. gattii based on culture and PCR analysis [28]. Six months after initial presentation and treatment with fluconazole (10 mg/kg PO q24hrs), the ferret developed CNS signs and was euthanized. Histopathological examination of the left eye of the ferret indicated the presence of cryptococcal organisms in the detached retina. Organisms were also noted in multifocal granulomas in the CNS and cranial mediastinum.
Two additional cases of cryptococcal lung involvement have been recorded in ferrets residing in Australia. In one case (case #10), the 2-year-old ferret presented with coughing. Radiography revealed alveolar disease and pleural effusion. The ferret died 2 hours after induction of anesthesia. Histology of the lung revealed granulomatous lesions in lung and mediastinal lymph nodes. Immunohistochemistry of lung tissue indicated that the cryptococcal organisms were C. neoformans. The Australian second case (case #11) had crytococcal lung disease with presenting signs of increased respiration and cyanotic mucous membranes. An abdominal mass was also palpated. The animal was anesthetized but succumbed to cardiac arrest. Histologic exam of the mass in the jejunum and the enlarged mediastinal lymph nodes indicated the presence of large numbers of cryptococcal yeast organisms identified by immunohistochemistry as C. neoformans. Granulomas containing cryptococcal organisms were widespread in the lung.
Three other cases (cases #12–14) of Cryptococcus spp. were noted in ferrets (one from Australia and two from Vancouver Island) with subcutaneous lesions located on the distal forelimbs. Both ferrets residing on Vancouver Island had biopsies taken from the masses and crytococcosis was confirmed by IHC. In one case, the firm ulcerative mass was surgically removed and appeared to be curative 4 months post operation. The second ferret with swelling of the distal forelimb and a draining popliteal lymph node was placed on fluconazole (12 mg PO q 12 hrs) and was eating normally 4 months after completing therapy. The ferret residing in Australia had a swollen distal left forelimb, and was lethargic with a poor appetite. An impression smear of the lesion stained with Diff-Quik demonstrated pyogranulomatous inflammation and cryptococcal-like yeast. Serum cryptococcal antigen titer of >2048 was recorded. Treatment with itraconazole (25 mg PO q 24 hrs) was instituted and the ferret responded quickly. The involved limb was normal within 5 weeks. After 6 months of itrazonazole, the titer was nil and therapy was discontinued.
Treatment
Until recently, a diagnosis of ferret cryptococcosis has only been made postmortem, and treatment was not attempted or the ferret died shortly after therapy was instituted. In case #5, the ferret with C. gattii was treated successfully with itraconazole. The ferret was initially treated with itraconazole suspension (Sporonox; Janssen Pharmaceutical, Titusville, NJ) 1.5 mg/kg bw PO q 24 hours for 3 weeks. The ferret's enlarged lymph decreased in size and its titer to cryptococcal antigen dropped from >2 : 4096 to 1 : 64. The ferret was switched to oral beads of itraconazole (∼15 mg) mixed in cat food for another 6 weeks. The ferret's lymph node returned to normal size with no signs of regurgitation. Two other ferrets with subcutaneous cryptococcal granulomas on the forelimbs were successfully treated, one with fluconazole, the other with itraconazole. A third ferret had a forelimb mass diagnosed as cryptococcal granuloma surgically removed and was clinically normal 4 months post surgery. Another ferret (#6) with cryptococcus subcutaneous granuloma on the nares was also successfully treated with surgery and itraconazole. Oral dosing with 25 mg of itraconazole mixed in palatable nutrient supplement was administered for 3 weeks; after 171 days post treatment, there was no sign of nasal cavity disease, nor swelling of the nasal bridge canal, and the latex cryptococcal antigen agglutination test (LCAT) titer had declined to 1 : 128. At 10 months post therapy, the titer in the ferret was 1 : 16 and ranged from 1 : 16–32 up to 3 years from the start of therapy [25]. Itraconazole was discontinued at this time due to presumed toxicity to the ferret. Three months later, an abdominal mass was detected, and the animal was euthanized. Multiple cystic hepatic lesions were diagnosed as scirrhous bile duct carcinoma. Histological examination of CNS, nasal cavity, and other tissue did not detect cryptococcal organisms [26].
It is important to note, however, that ferrets have been successfully treated with itraconazole at 10–20 mg/kg PO q 24 for a minimum of 10 months [19]. In other companion animals, treatment with AMB is sometimes used. In the cat, a dosage of 0.15–1.0 mg/kg, dissolved in 5–20 mL 5% dextrose and water, and given rapidly IV, 3 times weekly for 2–4 months, is used. The drug is nephrotoxic, and caution must be exercised to ensure proper hydration and monitoring of kidney function during the treatment period; antiemetics may also be needed [18].
Diagnosis
Cytological examination of tissue aspirates or impression smears of surgical tissue stained with Diff-Quik is straightforward and provides quick, reliable results. If cryptococcal meningitis is suspected, microscopic examination of the cerebrospinal fluid or involved tissue aspirate, mixed with India ink, if one is experienced with the assay, allows visualization of encapsulated budding forms of the fungus. Diagnosis is confirmed by cultural isolation of the organism on Sabouraud agar at 25°C and 37°C, or by histopathology and immunohistochemistry. DNA assays are also available, but specificity of the assay requires careful assessment. In Australia, a latex agglutination antigen-based assay is available to assess cryptococcal serum titers.
Pathology
In case #1, the serosal surfaces of adhered abdominal organs were covered with a colorless, jelly-like material that was easily removed from the underlying serosa. White nodules were present on the serosa of the intestine, in the parenchyma of the spleen, and in mesenteric lymph nodes and spleen. Histologically, masses of yeastlike organisms compatible with cryptococci, 10 μ in diameter and surrounded by a mucoid capsule, were observed in the jelly-like material adhering to the abdominal organs. Identical organisms were present in the cytoplasm of macrophages and multinucleated giant cells, which formed tubercle-like granulomata, and corresponded to the nodules seen on the small intestine at necropsy.
Histologic examination of case #2, with cardiomegaly, indicated changes in the heart, lung, and liver compatible with congestive cardiomyopathy and associated congestive heart failure [22]. A marked, diffuse, lymphocytic meningeal infiltrate involved the cerebral and cerebellar meninges. A moderate number of yeastlike budding organisms were seen in the inflamed meninges, compatible in size and shape to those of C. neoformans (Fig. 23.1 and Fig. 23.2). Histologic examination of pneumonic lungs in case #2 and lymph node in case #4 revealed thick-walled, budding yeasts, compatible with those of C. neoformans (Fig. 23.3, Fig. 23.4, and Fig. 23.5). In case #5, cytologic examination and culture of the enlarged submandibular lymph node indicated that the ferret lymph node was infected with C. gattii serotype A [29].
In case #6, Cryptococcus organisms were present on Diff-Quik stained smears. C. neoformans was cultured on Sabouraud's dextrose agar. The strain was identified as C. gattii and was susceptible to AMB, flucytosine, and itraconzole. A latex cryptococcal antigen agglutination titer of 1 : 1024 was documented.
Case #8 was necropsied and histology of the lymph nodes and spleen indicated that these tissues contained numerous spherical yeast organisms (12–25 μm diameter) consistent with Cryptococcus neoformans [27]. Organisms were surrounded by granulomatous to pyogranulomatous inflammation. Similar lesions were also present in brain, spleen, and multiple lymph nodes. DNA analysis of paraffin embedded tissue suggested that the organism was C. neoformans var. grubii (ITS type 1) [27]. Granulomatous lesions with cryptococcal organisms have been observed in the CNS, lymph nodes, and eyes (case #9), in the lungs (cases #10 and #11), as well as in subcutaneous tissues (cases #12–14).
Histoplasmosis
The disease is infectious, but not contagious, and is caused by an intracellular organism, Histoplasma capsulatum. It has been reported in dogs and cats [30]. In cats, histoplasmosis is the second most commonly reported systemic fungal infection [31].
Epizootiology and Control
In one recorded case, the ferret had been used to hunt rabbits and rats [32]. Its diet consisted of dog food, table scraps, and rabbit heads. The organism usually infects the host by the respiratory route, and exposure to aerosolized dust containing the organism is a probable mechanism of infection.
The disease in carnivores, particularly in the dog, is more commonly diagnosed in the central part of the United States, where the organism is commonly isolated from the soil. Interestingly, of the recorded ferret cases of histoplasmosis, one lived in Illinois, the other in Missouri [32,33]. Ferrets maintained in outdoor enclosures, and those used for hunting where the animal enters burrows in pursuit of prey, would more likely become infected with this disease. “Epizootics” of histoplasmosis arise from infected hosts sharing the same environment.
Clinical Signs and Pathology
One ferret with histoplasmosis presented with severe abdominal pain, marked splenomegaly, and subnormal temperature [32]. In another ferret, subcutaneous nodules were noted [33]. In humans, benign histoplasmosis may become acute and present clinically as pneumonitis, lymphadenopathy, anorexia, and weight loss. In dogs with disseminated disease, there is weight loss, hepatomegaly, splenomegaly, pneumonia, ascites, and generalized lymphadenopathy.
Diagnosis
Diagnosis in companion animals, and most likely ferrets, is difficult given that most infections are subclinical [30]. Biopsy of affected tissue and demonstration of the intracellular organisms by special stains, PAS, or Bauer's or Gridly's fungus methods help to establish a diagnosis. Culturing of the organism from infected tissues provides a definitive diagnosis.
Treatment
Treatment for histoplasmosis of ferrets has not been reported. In the dog and cat, the disease is treated with antifungal agents [30].
Pneumocystis carinii
Pneumocystis carinii was originally considered a protozoan and was first described by Chagas in 1909 when he misidentified them as Trypanosoma cruzi [34]. It was renamed as a new species, P. carinii, when observed in a rat in 1912 [35]. Several criteria were cited as supportive for its classification as a protozoan: (1) strong resemblance in microbe morphologic characteristics and host pathology, (2) absence of specific phenotypic features of fungi, (3) ineffective response to antifungal agents, and (4) effectiveness of antiprotozoal agents [36]. P. carinii, however, has now been grouped taxonomically with the fungi based on DNA analysis and the homology of P. carinii housekeeping genes with those found in fungi [36–38]. P. carinii is known to infect a number of mammalian hosts, including ferrets, rats, mice and humans. Although these organisms appear morphologically similar, there are antigenic and genetic differences among P. carinii isolated from different hosts [39,40]. Furthermore, studies indicate that P. carinii isolated from one host species is unable to survive and replicate after inoculation into a different immunodeficient host species [41]. The authors showed that P. carinii isolated from ferrets over a 2-year period were not capable of infecting scid mice. In contrast, using identical inoculation conditions, P. carinii was easily transmissible from one scid mouse to another [41]. These data, although not definitive, suggest that P. carinii pneumonitis in humans may not be acquired as a zoonosis, as previously speculated. These data are in contrast to reports suggesting that P. carinii isolated from humans was infectious to mice [42,43]. It is possible that the biology of P. carinii isolated from ferrets differs from that of P. carinii of humans, or alternatively, that the human P. carinii mouse transmission studies were complicated by subclinical, intercurrent infection in mice [44]. These DNA studies and apparent differences of host susceptibility prompted a new name, P. jiroveci, for pneumocystis isolated from humans [36,45]. P. carinii is now used to name the organism in rats and P. murina, the organism in mice. However, for the purpose of discussion we will refer to pneumocystis in ferrets as P. carinii.
Epizootiology and Control
Pneumocystis carinii inhabits the lungs as a commensal in various domestic and laboratory animals. However, its significance as a pathogen is recognized in hosts (both animal and human) that are immunocompromised, either by immunosuppressive drugs or by infectious agents that compromise the immune system; for example, HIV infections in humans [46,47]. Rats treated with corticosteroids, and nude athymic mice are used in experimental studies of this organism [48,49]. Animal models have also been used to demonstrate that Pneumocystis spp. can be transmitted via aerosol exposure [50,51]. These data suggest that in some cases, Pneumocystis spp. can be actively acquired and doesn't always reflect reactivation of latent infection [52,53].
Clinical Signs and Pathology
The ferret has also been used to study P. carinii pneumonia [54]. Ferrets were immunosuppressed by long-term administration of cortisone acetate 10–20 mg/kg subcutaneously for 9–10 weeks. Microscopically, P. carinii was observed in all 11 treated animals, producing extensive disease in 6 of the ferrets. The life cycle of P. carinii is completed within the alveoli of the lungs. Histologically, lesions consist of interstitial pneumonitis, focal mononuclear cell infiltrates, and abundant cysts and trophozoites focally distributed, which are clearly demonstrable using Gomori's methenamine silver nitrate (GMS) and Giemsa stains. Although abundant trophozoites were readily seen using these stains and paraffin-embedded thick sections, fine detail of the organisms was best demonstrated in thin, 1 μm plastic sections [54].
The ferret, like humans, is resistant to body weight loss from administration of corticosteroids. Stokes and colleagues [47,54] also noted that the ferret appears to be relatively susceptible to corticosteroid-induced P. carinii pneumonia. Pneumocystis pneumonia should, therefore, be considered in a differential diagnosis in ferrets on long-term steroid therapy or in those select ferrets suffering from hyperadrenocorticism, whose cortisol levels are high.
Diagnosis
Diagnosis of pneumocystosis in the ferret can be accomplished by bronchoalveolar lavage and subsequent demonstration of the trophozoites in the aspirated bronchoalveolar fluid. PCR-based assays are also available [55]. This assay should prove useful in studying anti-pneumocystis immunomechanisms in healthy hosts and provide insights to the pathogenesis of pneumocystis pneumonia in immunocompromised hosts [55]. This fungus has also been diagnosed histologically in the lung of a ferret experimentally infected with influenza virus [56].
Treament
Treatment with oral trimethoprim-sulfamethoxazole continues to be effective against P. carinii pneumonia in ferrets, as it is in humans and rats [54,57]. Pentamidine isethionate is also an effective drug for treating acute pneumocystis pneumonia in humans [58].
Mucormycosis
Mucormycosis is an opportunistic mycotic infection caused by a number of mold species of the order Mucorales of the class Zygomycetes. The disease was reported in ferrets raised for fur in New Zealand [59]. Otitis media is associated with primary otitis externa infection with Otodectes cynotis and with secondary fungal infection by Absidia corymbifera (ramosa). It has also been seen in cases of humans with diabetes mellitus. In humans, murcormycosis is the most common invasive mycosis in patients with hematological and allogeneic stem cell transplantation [60].
Epizootiology and Control
The prevalence in New Zealand ferret farms is reportedly common; on four farms, the infection rate ranged from 0.3% to 30%. Absidia corymbifera, a thermotolerant saprophyte, is not normally found in ferret ears, but is widespread in the environment. Control of the infection relies on regular examination of the ears and on aggressive therapy to eliminate ear mites. Moldy litter (hay and straw) should be avoided. Regular disinfection of ferret cages is also required.
Clinical Signs and Pathology
Scratching and irritation of the external auditory canal, indicative of mite infestation, is observed together with brown granular debris containing ear mites and fungal hyphae. Clinically, the animals can present with depression and lethargy. Torticollis, with the affected side of the head turned toward the body, loss of balance, circling, and prostration are occasionally observed. Necrosis and granulomatous inflammation of the petrous temporal bone, along with granulomatous meningoencephalitis, are sometimes present. Focal lesions in the temporal and pyriform lobes of the cerebrum and adjacent areas of the cerebellum and brain stems are also seen [59].
Diagnosis
Diagnosis is based on the demonstration of ear mites and Absidia hyphae in the external auditory canal. Aspiration biopsy of regional lymph nodes, and the presence of Absidia in histopathologic tissue section, in addition to positive culture, helps to confirm a diagnosis.
Treatment
The susceptibility of Absidia spp. to antimycotic agents is variable and poorly documented [61]. Antibiotic therapy instituted for suspected bacterial otitis externa may predispose these animals to secondary fungal infection. Treatment of mites is essential.
Malassezia spp.
Malassezia spp. are the most common yeasts associated with the unsuccessful resolution of otitis externa or otitis interna in dogs caused by primary diseases such as parasites, hypersensitivities, foreign bodies, glandular disorders, and keratinization disorders [61]. A brief description of Otodectes cynotis with secondary yeast infection caused by Malassezia sp. has been reported in a number of ferrets in England [62].
Epizootiology and Control
Eight of 50 ferrets developed crusting and necrosis of the pinnae [62]. Its apparent contagiousness was demonstrated when the disease spread to another six ferrets. The primary pathogen appeared to be Otodectes cynotis ear mites with the yeast being an opportunistic pathogen. Subsequent outbreak occurred in the same ferrets when the owner moved to a new location.
Clinical Signs and Pathology
Bilateral crusting and necrosis of the pinnae occurred, which, if left untreated, spread to the face in several animals. All animals had concurrent otitis externa. Severity of pinnae involvement, despite topical treatment with betamethasone, neomycin and monosulfiram, necessitated surgical removal of affected areas of the pinnae [62]. Involved epidermis contained inflammatory cells and yeasts beneath the corneum but no acanthosis. Large areas of necrosis and hemorrhage were associated with thrombosis.
Diagnosis
Mites are easily visualized from material collected from the ear canal (see Chapter 22). Yeasts consistent in morphology with Malassezia sp. were observed on impression smears [61]. The yeasts are 3–8 μm in diameter, usually round or oval, and often seen in clusters or adhered to keratinocytes [61].
Treatment
Oral ketaconazole at 5–10 mg/kg twice a day and topical application with miconazole, polymyxin B, and prednisolone resulted in marked improvement within five days of instituting treatment [61,62]. Contact ferrets were also treated. In dogs, treatment is continued 7–10 days beyond resolution of clinical signs [61]. The underlying mite infestation must also be effectively treated to prevent recurrent yeast infections.
Dermatomycoses
The most common causative agents of ringworm in domestic animals are Microsporum canis and Trichophyton mentagrophytes. The dermatophytes are grouped taxonomically as related fungi that have an affinity for cornified epidermis, hair, horn, nails, and feathers [61].
Epizootiology and Control
Dermatophytes are distributed worldwide, with some species more commonly reported in certain geographic areas. In an outbreak of ringworm in mink, cats were allowed to sleep in nest box bedding stored for mink kits. The cats were suffering from clinical cases of ringworm. Cats may also have been involved in an outbreak of ringworm in a ferret colony [63].
Dermatophytes are usually spread from animal to animal by direct contact, or indirectly by contaminated fomites. Concentration of ferrets in limited housing also enhances the probability of the spread of infection.
Control of infection depends on removal of infected animals from the premises and disinfection or destruction of all contaminated bedding, caging, and other potentially contaminated materials.
Transmission of dermatophytes from animals to humans is a well-known and serious public health concern. Ferrets with ringworm therefore present a zoonotic risk, and care should be exercised by personnel who handle infected animals [64].
Clinical Signs and Pathology
Younger animals are at higher risk to develop clinical disease. Lesions appear as circumscribed areas of alopecia and inflammation distributed on all areas of the skin (Fig. 23.6). The skin is thickened, inflamed, and covered by scaly crusts.
Diagnosis
Presumptive diagnosis is based on suspicious skin lesions that begin as small papules and spread peripherally, leaving scaly inflamed areas of alopecia. Examination of the lesion under ultraviolet light (Wood's lamp) for yellow-green fluorescence is helpful in diagnosing infections caused by Microsporum canis. Trichophyton spp. do not fluoresce. Microscopic examination of skin scrapings containing scales and hair, using 10% potassium hydroxide, shows characteristic arthrospores. Definitive diagnosis requires culture of the fungus on dermatophyte test medium or Sabouraud's agar.
Treatment
Clinical signs may regress without treatment. Griseofulvin, 25 mg/kg given orally, however, also results in remission of clinical signs of ringworm in the ferret [63].