Feline Systemic Fungal Infections

INFECTIOUS DISEASE AND THE EYE

0195-5616/00 $15.00 + .00

FELINE SYSTEMIC FUNGAL INFECTIONS Juliet R. Gionfriddo, DVM, MS

Systemic fungal infections are uncommon in cats; however, they are reported with increased frequency and are important diagnostic differential considerations in sick cats, especially cats with uveitis. This article reviews the available literature on disseminated fungal infections in cats, focusing on the ocular manifestations of these diseases. Much of this review concerns cryptococcosis because it is the most common feline disseminated fungal infection18 and the focus of much research. The treatment regimens for cryptococcosis that are discussed herein are recommended by clinicians and researchers. These regimens involve the use of systemic antifungal medications that are used to treat many different fungal infections, and the reader may apply the information in the cryptococcosis section for use in animals with other systemic mycoses. The incidence of ocular involvement in disseminated fungal disease in cats is unknown. Many reports do not mention whether an ocular examination was performed; therefore, the numbers of cats with ocular lesions may be much higher than previously reported. In most cases of systemic mycoses with ocular lesions, the uveal tract is involved in the disease process. This observation suggests that the fungal organism arrives at the eye hematogenously and lodges in the small vessels, usually of the choroid. In all systemic mycoses, intraocular inflammation is caused by the presence of the organism within the eye rather than occurring as a secondary inflammatory response to systemic infection (Robert English, DVM, PhD, personal communication, 2000). The unique immunologic defense mechanism of the eye may allow fungal organisms such as Blastomyces to persist in ocular tissues. 23 The eye has an alternate immune response known as the anterior chamber-associated immune deviation. This deviant immune response results in antigen-specific suppression of delayed-type hypersensitivity, the main mech-

From the Department of Clinical Sciences, Colorado State University, College of Veterinary Medicine, Fort Collins, Colorado

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 30 • NUMBER 5 • SEPTEMBER 2000

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anism by which the body rids itself of fungal organisms. 23 The anterior chamberassociated deviation is thought to have evolved to prevent excess inflammation in the eye and to prevent killing of normal tissues. 23 This system is disadvantageous in that it limits the ability of the eye to eliminate certain pathogens such as fungi, parasites, and intracellular bacteria. 23 In many systemic fungal infections, the organism may remain in the eye, and the eye can serve as a reservoir of reinfection. 23 This fact has prompted some ophthalmologists to recommend the removal of infected eyes that do not respond to antifungal therapy. CRYPTOCOCCOSIS Pathogenesis

Cryptococcosis is an important opportunistic infectious disease of mammals throughout the world. It has been reported in domestic cats from Australia, Austria, Canada, Hawaii, Japan, New Zealand, Papua New Guinea, the United Kingdom, and the United StatesP Although once considered a rare disease in cats, the abundance of published case reports and retrospective and prospective studies of feline cryptococcosis over the last few years suggests that it can no longer be considered uncommon. Cryptococcosis is the most frequently recognized systemic fungal infection in cats. 5• 8• 5 4. 57• 73 It accounted for 263 of 571 (46.1%) cases of deep mycotic infections identified from the Veterinary Medical Database, the literature, and the hospital population of the Virginia-Maryland Regional College of Veterinary Medicine from March 1964 through May 1994.18 Cryptococcosis is caused by the yeast-like basidiomycete fungus Cryptococcus neoformans. Two varieties are recognized, C. neoformans var. neoformans and C. neoformans var. gatti. Both varieties cause disease in cats, 52 but C. neoformans var. neoformans is responsible for almost all of the disease in the United States and Europe. 64 C. neoformans is saprophytic and has been isolated from the skin, oropharynx, and gastrointestinal tract of healthy humans and from soil, fruit juice, milk, wasp nests, grass, insects, butter, and pigeon droppings. 5• 22 Pigeon droppings provide nutrients (creatinine and nitrogen) important for growth of the organism. 8• 22• 87 Although C. neoformans passes through the intestinal tract of pigeons, avian cryptococcosis does not occur because the body temperature of pigeons is too high to allow reproduction of the organism. 57• 87 C. neoformans can remain viable for at least 2 years in pigeon droppings in moist environments,S7 thus pigeon droppings provide a major reservoir of the organism, particularly in urban areas. They were the known source of infection in two feline cases. 5 7 In Australia, a major reservoir is thought to be decaying plant matter in the hollows of fig trees. 46• 54 Cryptococcus organisms are round to oval and thin walled, with a cell diameter of 2.5 to 8 f.L in laboratory cultures and up to 15.0 f.L in tissues. 8• 39 Each organism has the ability to form a large thick heteropolysaccharide capsule that confers virulence and resistance to desiccation. 39 C. neoformans reproduces asexually in tissues by single or multiple budding. 8• 39 Recent evidence suggests that C. neoformans var. gatti reproduces sexually in the wild. 32• 54 C. neoformans var. neoformans may be evolving into an asexual fungus, and the infectious particle, the basidiospore, may result from asexual fruiting and sexual recombination. 43• 54 The basidiospore is adapted for dispersal by air and has properties that allow it to adhere to and penetrate the respiratory epithelium and infect the hosf.54

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Although the exact mode of transmission of cryptococcosis is unknown, most evidence suggests that it occurs via inhalation of aerosolized basidiospores.39· 54• 57· 86· 87 In cats, the nasal cavity is usually the primary site of infection.52-54 Tumquesf86 was unable to infect cats by injecting organisms subcutaneously, intraperitoneally, or orally, and succeeded only by intranasal, intratracheal, or intrathecal injections. Once inhaled, the organism regenerates its capsule, lodges in the nasal passages, and begins infection as a mycotic rhinitis. 54 If the rostral portion of the nasal cavity is involved, clinical signs such as sneezing, wheezing, and nasal discharge are prevalent53· 54 If the strain of C neoformans is highly invasive, the fungus may destroy the adjacent facial bones and spread to contiguous regions such as the nose and hard palate. This invasion produces facial lesions such as distortion of the nasal cavity. 25• 52· 73· 87 If the infection begins in the caudal portion of the nasal cavity, clinical signs of mycotic rhinitis may be absent, but the infection may spread through the cribriform plate and into the olfactory bulbs and olfactory tracts, thereby causing meningitis. 18· 25· 36· 54· 60 Involvement of the optic nerves also may occur, leading to cryptococcal optic neuritis with clinical signs of papillitis, blindness, and dilated fixed pupils. 18· 25· 36· 54• 60 Hematogenous dissemination from the nasal cavity leads to multifocal cutaneous lesions, chorioretinitis, or both. 7· 54 Extension of the organism to the eye can occur from optic nerve meningitis, but the multifocal nature of the chorioretinitis lesions in the naturally occurring disease of cats suggests that hematogenous spread to the choroid is the most common route of ocular infection?· 8 In experimental infections in cats, when large numbers of organisms are injected into the carotid artery, the organisms shower the eye and consistently produce typical multifocal chorioretinitis lesions. 7 In humans, there is a predilection for cryptococcal and other deep mycotic infections in individuals who are immunosuppressed. 51· 59 Cryptococcosis occurs in immunocompetent individuals also; in these individuals, it is caused almost exclusively by C neoformans var. gatti. 54• 64• 84 It seems logical that cats infected with immunosuppressive viruses such as feline leukemia (FeLV) and feline immunodeficiency virus (FIV) would be predisposed to developing cryptococcosis. Recent studies have examined the possible influences of FeLV and FIV on the susceptibility of cats to cryptococcal infection and the ability of these viruses to influence the course of disease. 18· 25• 38• 51· 52· 60 In most of these studies, in cats naturally infected with cryptococcosis, the incidence of concurrent FeLV infection was low (ranging from 0% to 9.2%), as was the incidence of concurrent FIV infection (ranging from 0% to 28% ). 18· 25· 52· 60 Although in one study in Australia the incidence of concurrent FIV and cryptococcal infection was high (28% ), this rate was not significantly different from the rate for the population of "sick" cats in Australia or from the incidence among randomly selected healthy cats in the area. 52 Infection with FeLV or FIV does not seem to predispose cats to disease from C neoformans. Mancianti and co-workers51 looked for C neoformans in the orophamyx in FlY-seronegative cats and FlY-seropositive cats. 51 They found no organisms in any of the 55 FIV-negative cats whereas 6 of 35 FlY-positive cats had C neoformans present in the oropharynx.51 None of these six cats had clinical symptoms of cryptococcosis.51 These results suggest that FIV-infected cats carry C neoformans more commonly than noninfected cats. 51 Although immunosuppressive viruses do not seem to predispose cats to cryptococcosis, evidence suggests that cats with cryptococcosis and a concurrent viral infection may have a less favorable prognosis 38· 60 and may require lengthy treatment with antifungal agents.38 Immunosuppressive factors are not always associated with a poor outcome for the cat 25• 52 Malik and co-workers52 found that many FlY-seropositive cats with cryptococcosis could be "cured" with

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fluconazole therapy, and that these cats did not relapse when the drug was discontinued. Genetic factors may influence the susceptibility of cats to cryptococcosis. In some studies, infection rates for male cats have been significantly higher than the rates for females, 38· 52 whereas other studies have found no sex predilection. 39 Siamese cats are overrepresented in clinical reports and retrospective studies. 18· 52· 76· 88 Cryptococcosis can affect cats of any age, but the majority are between 3 and 7 years (average, 5 years)?· 8 The first published report of feline cryptococcosis appeared in the early 1950s.'7 Since then, numerous case reports from many countries have been published.* Ocular lesions have been described as part of the disease in only a few of these reports. 20· 24· 30· 55· 76· 87 Subsequent retrospective and prospective studies of naturally occurring infections and studies of experimentally infected cats have shown that many animals affected with disseminated cryptococcosis have ocular lesions?· 18· 38· 52· 60 In one study of 18 cases of systemic cryptococcosis in which cats had ocular examinations, 9 had ocular lesions? These lesions consisted of chorioretinitis, optic nerve papillitis, or both. These results suggest that there may be a higher incidence of ocular involvement in cats with systemic cryptococcosis than has previously been suspected. The presence of ocular cryptococcosis may be difficult to detect without fundic examination, and veterinarians have not always examined the fundus in these sick cats.

Clinical Signs Systemic

Cryptococcosis in cats usually involves the nasal cavity, skin, and subcutis, the central nervous system, and the lymph nodes. The most frequently reported symptoms are attributable to mycotic rhinitis and include sniffling, sneezing, wheezing, and nasal discharge (unilateral or bilateral).5· 18· 25· 52· 59· 60· 73· 87 Malik and co-workers52 found that 83% of 29 cats in their study had nasal cavity disease. Davies and Troy reported that 63% of the 571 cats in their retrospective study had nasal discharge and 12.5% cough or dyspnea. 18 Involvement of the structures adjacent to the nasal cavity is a frequently reported manifestation of feline cryptococcosis. 18· 25· 52· 54• 57· 60· 69· 73· 87 Clinically, this involvement appears as a deformity of the face (described by many as a domeshaped swelling) usually involving the bridge of the nose, side of the face, and areas over the sinuses or on the upper lip.8· 18· 25· 57· 60· 69· 73· 87· 88 These lesions are usually subcutaneous nodules, but some ulcerate and lead to dermallesions.8· 68 Occasionally, the organism invades the nasal bones. Other lesions described in cats with nasal cryptococcosis are fleshy masses protruding from the nasal cavity.5· 18· 25· 57 Radiographs of the nasal cavities of cats sustaining cryptococcosis are often normal or may show only soft-tissue masses, depending on the degree of bony involvement.8· 61 Multiple cutaneous nodules occur in many cats with disseminated cryptococcosis.18· 25· 54· 57· 68· 87 In a study of 571 cryptococcosis cases, 41% of cats had cutaneous nodules as a manifestation of the disease. 18 Other studies have reported similar proportions of infected animals with cutaneous lesions. 25• 38• 57 The nodules are usually described as fluctuant, raised, dome-shaped, and erythema*References 5, 13, 20, 21, 24, 30, 33, 35-37, 45, 47, 55, 61, 68, 73, 80, and 87.

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tous. 81 They frequently ulcerate and ooze a grayish gelatinous exudate, 45• 68• 81 or they may be granulomatous. 45• 81 Cryptococcal meningitis is thought to occur primarily from direct extension of the organism through the cribriform plate. 54 It can also occur by hematogenous spread, as has been reported in humans. 49 Blouin6 was unable to produce optic nerve meningitis in cats by direct intracarotid injection of cryptococcal organisms. 6 She concluded that papillitis was associated with brain involvement with subsequent optic nerve meningitis. 6• 7 Meningitis may occur without other apparent systemic signs and can mimic diseases such as toxoplasmosis, trauma, and neoplasia?· 52• 73• 87 Clinical signs of meningoencephalitis include blindness or vision problems, 18• 25• 36• 52• 57• 60 dilated and fixed pupils, slow pupillary light reflexes, 18• 25• 59 depression, ataxia/5• 57• 73 temperament changes, and disorientation. 57• 60 Ocular examinations of cats with blindness owing to meningitis usually reveal inflammation of the optic nerve heads (papillitis),8• 87 consisting of marked congestion, tortuosity of retinal vessels, peripapillary retinal hemorrhages, and, occasionally, peripapillary retinal detachment. 8• 87 One acutely blind cat with cryptococcosis had a tissue mass impinging on both optic nerves which was thought to have caused the blindness rather than meningitis. 36 Lymphadenopathy is a prominent feature in many cases of feline cryptococcosis and was found in 39% of the 571 cases described by Davies and Troy. 18 It is most commonly found in conjunction with other manifestations of the disease. Cryptococcosis can also present with signs that are less commonly reported, including aural granulomas, 68 orallesions/8 pyothorax, and lameness owing to long bone lesions. 8 Pulmonary involvement is rare. In most cases of disseminated cryptococcosis, multiple tissues are involved in the disease process. Ocular

The most frequently reported ocular manifestations of cryptococcosis are various degrees of chorioretinitis. 8• 18• 20• 24• 30• 57• 76• 87 Cryptococcal chorioretinal lesions may be single or multifocal. They begin as pinpoint round opacities that enlarge to form circular areas8 (Fig. 1). The lesions within the tapetal area are often described as almost clear early in the course of the disease.6-8 Rosenthal and co-workers76 described the chorioretinallesions in a Siamese cat with ocular and systemic cryptococcosis as being multiple, small, irregular, gray, and punctate. Lesions may range in size from 0.25 to 1.5 disk diameters. 8 Larger lesions may be elevated and cause distortion of the overlying retinal vessels. 8 The chorioretinallesions found in cats with experimentally induced cryptococcosis were almost identical to the lesions observed in naturally occurring cases. 7 In the experimental cats, the clear lesions became dark and indistinct as the disease progressed. 7 In severely affected experimental cases, the whole fundus became involved and the retina detached? In the experimental cats, the severity of the chorioretinitis was directly associated with the number of organisms reaching the globe. 7 This relationship may exist in naturally occurring cases. Anterior uveitis (iridocyclitis) has been present in most of the reported cases of feline cryptococcosis with chorioretinitis. 8• 24• 30• 76 Iridocyclitis ranges from mild to severe. Clinical signs include keratic precipitates, fibrin in the anterior chamber, fibrin and pigment on the anterior lens capsule, and posterior synechiae. 8• 24. 30 In most cases, anterior uveal signs are probably secondary to disease in the posterior segment. Optic neuritis is the second most commonly reported ocular lesion in cats with cryptococcosis. 18 Other ophthalmic signs reported in naturally occurring

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Figure 1. Multifocal chorioretinitis lesions in a cat with cryptococcosis. (Courtesy of Jean Stiles, DVM, West Lafayette, IN.)

cryptococcosis cases have included exophthalmos owing to a retrobulbar abscess, 60 H orner's syndrome secondary to an aural mass, 68 swelling of the conjunctiva, severe thickening and protrusion of the nictitating membranes (Fig. 2),55 and ocular discharge.8• 37• 76 The discharge w as either serou s (epiphora) or purulent and was reported in cases with and without other know n ocular disease. In the cat with ocular lesions described by Rosenthal and co-workers/ 6 the discharge was initially serous but became purulent as the disease progressed. The

Figure 2. Thickened, inflamed conjunctiva and third eyelid in a cat. Cryptococcal organisms were present in large numbers in the conjunctiva of both eyes, although intraocular structures were normal. (Courtesy of Jean Stiles, DVM, West Lafayette, IN.)

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cause of the discharge has not been reported in most studies and, in some cases, may have been a nonspecific sign of illness or a response to ocular pain. One cat inoculated experimentally with large numbers of C. neoformans organisms had a chronic ocular discharge. The organism was isolated from the conjunctival sac. 7 The investigators in that study attributed its presence to an extension of a nasolacrimal infection? Diagnostics

Cryptococcosis should be suspected in any cat with clinical signs of nasal discharge, deforming facial lesions, nasopharyngeal disease, multiple cutaneous nodules, peripheral lymphadenopathy, blindness, chorioretinitis, intracranial disease, spinal cord disease, pyothorax, or middle ear disease. 8• 18• 54 Definitive diagnosis is determined by culturing the organism in a reliable laboratory. 54 A presumptive diagnosis can be made by demonstrating the organism on stained smears of nasal swabs or washings, needle aspirates of cutaneous nodules or enlarged lymph nodes, pleural fluid, cerebrospinal fluid (CSF), or aspirates of vitreous or subretinal space.8• 18• 25• 52• 54 These smears can be stained with a twostep stain such as Quik-dip (Mercedes Medical, Sarasota, FL), Wright's, or new methylene blue and then examined microscopically for the presence of thickly encapsulated, broad-based budding yeast cells. 54• 57 Although some researchers suggest that staining with India ink may highlight the capsule and aid in diagnosis, other believe that such staining may be less reliable because white blood cells, fat droplets, and ink particles may also be highlighted and mistaken for organisms. 59 In cases in which ocular involvement is prominent and the organism cannot be isolated from other tissues, a vitreous or subretinal fluid aspirate may contain the organism. 30 In histopathologic studies of enucleated cat eyes with cryptococcal chorioretinitis, the pathogen has usually been found in large numbers in the subretinal space and in smaller numbers in the vitreous 8• 24• 30; therefore, vitreous samples are often diagnostic but do not always yield organisms. 59 Aspirates obtained from the subretinal space of cats with chorioretinitis usually contain organisms. Aspirates of aqueous humor rarely contain the organism even if anterior uveitis is presenU· 8 Often, cryptococcal organisms are not found in the anterior segment on histopathologic examination of infected eyes, even if they are found in large numbers in the posterior segment'· 24• 3°Cats experimentally infected with a large inoculation [8 X 108 colony-forming units (CFU)] have organisms present in the iris and ciliary body, whereas cats infected with smaller numbers (8 X 101 or 8 X 105 CFU) do not. 6 It is likely that organisms would be present in the anterior segment and be retrievable by aqueous centesis only in the most severe cases of naturally occurring disease. 24• 30 Malik and co-workers54 have stressed the importance of determining the variety of C. neoformans causing the infection and its susceptibility to antifungal agents. They recommend the culturing of lesions from all cases because infections caused by C. neoformans var. gatti typically are more severe and more refractory to antifungal drugs than infections caused by var. neoformans. 54• 64• 84 In addition, C. neoformans var. gatti strains may be more susceptible to itraconazole than ketoconazole. 54 It may be less important to determine the variety of organism in North America because C. neoformans var. gatti occurs mostly in Asia, Africa, South America, and Australia. 64 In vitro testing of organisms for sensitivity to antifungal drugs is not thought to be as accurate as antibacterial susceptibility testing54; however, fungal

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sensitivity tests may provide useful information regarding therapy. Strains that have a low minimum inhibitory concentration for a drug in vitro may also be susceptible to the drug in vivo. 54 Histologic examination of biopsy specimens from affected tissues is a good way to diagnose cryptococcosis antemortem. 25' 54, 57, 59 With hematoxylin and eosin stain, the organisms in tissues appear as round to oval eosinophilic bodies surrounded by halos (capsules).57 Mayer's mucicarmine is the definitive stain for cryptococcal organisms because it colors the capsules red but does not stain other fungi that have similar morphologic characteristics.57 When the organism cannot be isolated or when obtaining a tissue or fluid sample may jeopardize the patient's health (e.g., CSF collection in debilitated animals with symptoms of meningitis only), serologic testing may be useful. 54, 58 The cryptococcal antigen latex agglutination system is a highly specific and sensitive test to detect cryptococcal capsular antigen. 58 This test can detect the antigen in serum, urine, and CSf.58 The author could find no information regarding the ability of the test to detect antigen in the vitreous or aqueous. Serologic testing is useful for determining the severity of infection (the higher the titer, the more severe the infection) and for monitoring the progress of therapy. 58 A good prognosis is indicated if the antigen titer decreases during therapy. 59 Falsenegative results have been reported with the latex agglutination test but are rare. 58 Several latex agglutination test kits are available for use in private practice.39 Therapy

As is true in all cases of uveitis, therapy should be directed at treating the specific cause and the uveitis symptomatically. Before systemic treatment is initiated, the diagnosis of cryptococcosis should be confirmed. Antigen titers should be obtained in all cats to monitor the progress of therapy. The best choice of antifungal drugs and the therapeutic regimen for each case are based on many factors, including the duration of the infection, the extent of invasion and dissemination of the organism, the tissues involved, the susceptibility of the strain of organism to antifungal drugs, and the age and physical condition of the cat (especially, its renal and hepatic function). 54 The temperament of the patient and the emotional and financial commitment of the owner to treatment are also important considerations.54 Five antifungal drugs are currently available for the treatment of cryptococcosis and other systemic fungal diseases in the cat: amphotericin B, flucytosine, ketoconazole, fluconazole, and itraconazole.54 Until recently, amphotericin B, a polyene antibiotic with antifungal activity, was the treatment of choice for cats with systemic fungal disease (including patients with cryptococcal chorioretinitis). 16, 30, 39, 78 Its fungicidal properties make it a superior antifungal drug to the azole drugs, which are fungistatic. 54 Unfortunately, the use of amphotericin B is limited by the drug's many side effects, the most severe of which is nephrotoxicity.39 Another drawback is the fact that amphotericin B must be given parenterally, whereas other antifungal drugs can be given orally. Despite its shortcomings, amphotericin B is recommended in combination with 5-flurocytosine for cats with severe widely disseminated disease, especially when there is concurrent meningitis.54 Its use is contraindicated in cats with pre-existing renal disease. 5-Fluorocytosine (flucytosine) is a fluorinated pyrimidine that inhibits nucleic acid synthesis. It is given orally and is very effective against many fungi. Its main disadvantage when used alone is that many organisms develop rapid

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resistance. 39 Flucytosine penetrates the blood-brain barrier well and is particularly effective for central nervous system infections when used in conjunction with amphotericin B.8• 54 When used together, these drugs have a synergistic effect and decrease the nephrotoxicity associated with amphotericin B therapy. 8 Ketoconazole has been used extensively to treat cats with cryptococcosis. 20• 21 • 25· 33• 61• 68• 73• 85 Although it has been effective in many cases, including one in which the animal had cryptococcal chorioretinitis,20 side effects of anorexia, weight loss, vomiting, and depression are common?'· 25• 59• 60• 68• 73• 80 A prospective study of 47 cats naturally infected with C neoformans showed that ketoconazole was the most commonly used drug treatment, primarily because of its low cost, availability at the time, and ease of administration. 25 Only 9 of the 38 cats (23.7%) that received ketoconazole were free of clinical disease at the time of follow-up examination, and 47.7% had died or were euthanatized. 25 In contrast, 5 of 11 cats (48%) treated with itraconazole were free of disease. 25 Based on these results, it was concluded that ketoconazole is not the drug of choice for feline cryptococcosis. Itraconazole and fluconazole are effective in treating many cases of cryptococcosis.25· 59• 60 These oral triazole drugs inhibit the synthesis of ergosterol, the main sterol in the fungal cell membrane. 16 This disruption alters the fungal cell membrane and inhibits cell growth and replication. Fluconazole is extremely effective for treating disease caused by the majority of known isolates of C neoformans. 52• 54 It penetrates well into the brain, eye, and urinary tract. 16• 54 Malik and co-workers52 tested fluconazole in 29 cases of naturally occurring disease. Twenty-eight of 29 cats responded well, and there were virtually no side effects associated with use of the drug. 52 One cat that responded well had severe menigoencephalitis with optic neuritis. 52 Some cats with cryptococcal central nervous system disease do not respond to fluconazole therapy (Linda Medleau, DVM, MS, personal communication). The responses of cats with cryptococcal chorioretinitis to fluconazole therapy are unknown, but, because of its ability to penetrate the eye, a good outcome is expected. Fluconazole is very expensive, which limits its use in veterinary medicine. Itraconazole is more effective than ketoconazole for the treatment of feline cryptococcosis and has fewer side effects. 25• 54• 59• 60 Itraconazole is less expensive than fluconazole; consequently, it is the drug of choice for most cases of feline cryptococcosis.54 In a study of three cats experimentally infected with C neoformans, Medleau and co-workers59 found that itraconazole was effective in all cats. Although it did not penetrate well into the CSF, cats with cryptococcosis of the central nervous system responded well. 59 In a subsequent study of 35 naturally occurring cases of feline cryptococcosis,60 the treatment response to itraconazole was deemed as a success in 57% of the cats, as improved in 29% of cats, and as a failure in 4%. One cat in which the treatment failed had severe disseminated disease with signs of meningitis and chorioretinitis. 60 Although fewer side effects are associated with itraconazole than with other antifungal drugs, many cats develop reversible hepatotoxicity when itraconazole is given for long periods of time, especially in high doses. 54• 6°Clinically, this toxicity appears as anorexia and sometimes vomiting. 54· 60 Serum alanine aminotransferase is elevated. The itraconazole-induced hepatotoxicity may be reversed by discontinuation of the drug; up to 7 days may be required for the return of a normal appetite. 54 When appetite returns, itraconazole may be restarted at 50% of the dose originally given. 54 Monthly monitoring of serum alanine aminotransferase levels is recommended during itraconazole therapy to detect the onset of hepatotoxicity so that the drug can be discontinued or the dosage decreased before the onset of clinical signs. 60

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Therapy

Treatment regimens for cats with cryptococcosis have been published. 54 For cats that are eating and that have mild-to-moderate disease without central nervous system involvement, Malik and colleagues54• 60 recommend itraconazole at a dose ranging from 50 mg (for cats weighing less than 3.5 kg) to 100 mg (for cats weighing greater than 3.5 kg) orally once daily. Alternatively, cats weighing less than 3.5 kg can be given 100 mg every other day. 54 Jacobs and Medleau39 recommend giving cats 5 to 10 mg/kg twice daily. 39 Itraconazole should be given with food and may be sprinkled from the 100-mg capsule onto highly palatable wet food. 54 Fluconazole can be used instead of itraconazole in cases of mild and moderate disease and is the drug of choice in cats with liver disease. 60 An oral dose ranging from 25 mg (for small cats) to 50 mg (for larger cats) twice daily is recommended by Malik and colleagues,54 whereas Jacobs and Medleau39 recommend 5 to 15 mg/kg every 12 to 24 hours. Serum antigen titers should be monitored to determine the success of therapy. Usually, the antigen titer drops by a twofold dilution per month in successful cases. 54 If the titer does not decrease in response to therapy, more aggressive treatment should be instituted. 54 In cases of cryptococcal chorioretinitis, regression of the fundic lesions is an excellent indication that the cat is responding to treatment. 30 Systemic antifungal drugs should be continued until all symptoms of the disease are resolved and no organisms are gleaned from cytologic or histologic examination of affected tissues. 54 This improvement generally occurs within 2 to 6 months but may take considerably longer. 54 Once no symptoms remain, a serum sample should be taken for latex agglutination testing. If there has been a four to fivefold reduction in the titer, itraconazole should be continued (often at a reduced dose) until the antigen titer drops to 0. 54 If the titer has not been reduced enough, more aggressive therapy should be instituted. Jacobs and coworkers38 recommend that treatment with itraconazole should be continued for 1 month after the resolution of clinical signs and until serum antigen titers have decreased by at least two orders of magnitude from pretreatment values (but preferably until serum antigen is undetectable). According to Malik and colleagues,54 cats with severe disease, cats having meningoencephalitis (including cats with optic nerve meningitis), and cats that fail to respond to azole therapy should be treated aggressively with amphotericin B and flucytosine. These clinicians recommend giving amphotericin B two to three times a week subcutaneously with a large volume of fluid to allow slow absorption into the systemic circulation and to avoid the high peak blood levels that lead to nephrotoxicity. 54 These infusions are continued until the organisms are eradicated from tissues and there is major clinical improvement. 54 This process usually occurs within 6 to 12 weeks, by which time the patient is usually well enough to be switched to maintenance oral azole therapy. 54 Malik and colleagues prepare the drug for administration by reconstituting a 50-mg vial of amphotericin B with 10 mL of sterile distilled water and adding the calculated dose (0.5-0.8 mg/kg; about 0.4 to 0.8 mL} of this dilution to a 500-mL bag of 0.45% NaCl with 2.5% dextrose (warmed to 40°C} from which 100 to 200 mL has been removed. 54 All of the fluid in the bag is then rapidly administered subcutaneously between the scapulae through a 19- or 21-gauge needle. If discomfort occurs, the needle may be moved to another site.54 Flucytosine is administered orally during the amphotericin B therapy at a dose of 250 mg every 6 hours for large cats and every 8 hours for small cats. 54 Malik and colleagues recommend monitoring blood urea nitrogen and creatinine levels

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carefully during amphotericin B therapy and temporary discontinuation of the infusions if azotemia develops. 54 Controlled studies to determine the best treatment for cats with cryptococcal chorioretinitis and anterior uveitis have not been done. Empirical evidence suggests that, because of its ability to penetrate into the eye, systemic fluconazole may be the drug of choice in these cases. Nevertheless, veterinary ophthalmologists who treat the disease generally use itraconazole (Charles L. Martin, DVM, personal communication, 2000). Symptomatic ocular therapy should be instituted if uveitis is present. This therapy consists of using topical or systemic anti-inflammatory drugs or both and topical cycloplegic therapy. Topical anti-inflammatory medication should be used aggressively in cases of mycotic uveitis." These drugs treat mainly the anterior portion of the eye and are most effective if anterior uveitis is present. Generally, topical corticosteroids are not absorbed in high enough concentrations to suppress systemic immunity, thus they may be used in cats with systemic fungal infections. Prednisolone acetate (1%) and dexamethasone ophthalmic (0.05% to 0.1%) suspensions are potent anti-inflammatory drugs that enter the anterior chamber in therapeutic concentrations.82 For severe uveitis, these drugs may be given six times daily until symptoms subside. The dosage may then be reduced to a twice or thrice daily maintenance schedule. Topical steroids are contraindicated if a corneal ulcer is present. Nonsteroidal topical anti-inflammatory drugs, such as flurbiprofen sodium 0.03%, suprofen 1%, diclofenac 0.1%, and ketorolac 0.5%, are important components of therapy and may be used alone or in conjunction with topical steroids.82 In cats, these agents may be used two to three times daily. Systemic anti-inflammatory drugs should be used with care in cats with systemic fungal disease. Systemic corticosteroids are rarely advocated, and most experts consider them contraindicated. 82 Nonsteroidal systemic anti-inflammatory drugs such as aspirin may be used with care in cats. The dosage is 10 mg/ kg every other day with reduced dosage after symptoms subside. 82 Such drugs are contraindicated if there is anorexia, renal disease, or gastrointestinal involvement. Topical cycloplegic drugs dilate the pupil to help prevent posterior synechiae and also help alleviate pain by paralyzing the ciliary body muscle. The cycloplegic drug of choice is atropine ophthalmic. It should be used to effect (often enough to keep the pupil dilated), which initially may be as often as four to six times daily. Atropine is very bitter and after topical application may travel down the nasolacrimal system into the mouth, leading to intense salivation in cats. For that reason, topical atropine ointment may be a better choice for cats. Enucleation has been advocated by some clinicians to treat systemic mycoses with ocular involvement.28• 29 In general, blind painful eyes of cats with systemic mycoses should be removed. This surgery not only alleviates pain but removes a nidus for the dissemination of sequestered organisms and the recurrence of infection. 11• 28 Even if the disease is treated and resolves, the prognosis for return of vision is guarded. In most cases, the subretinal and intraretinal granulomas disappear, but the retina may be damaged enough that vision does not return. In other cases, vision may be partially spared." The author could find no information on the ocular response to therapy in cats with mycotic ocular disease. In dogs with blastomycosis, Brooks and co-workers11 found that animals with subretinal granulomas, retinitis, or chorioretinitis were likely to respond positively to therapy, whereas dogs with optic neuritis were not.

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HISTOPLASMOSIS Pathogenesis

Histoplasmosis is caused by the saprophytic dimorphic fungus Histoplasma capsulatum. The species occurs worldwide in temperate and tropical climates and has been found in 31 states of the continental United States.44• 91 • 92 Histoplasma capsulatum is commonly reported in the states of the Ohio, Missouri, and Mississippi river valleys and is widespread in Texas. 91• 92 It grows best in nitrogen-rich soils containing bird and bat droppings. 44• 91 In the soil, the free-living mycelial stage of H. capsulatum produces two types of fruiting bodies: (1) macroconidia (5 to 18 fLm in diameter) and (2) microconidia (2 to 5 fLm). 92 Infection occurs by inhalation of microconidia, which transform into the yeast phase in the lungs. The yeast cells are phagocytized by the pulmonary macrophages. 15 Cats usually remain clinically normal despite the development of a transient infection of the lungs and pulmonary lymph nodes. 15• 91 • 92 In some cats, H. capsulatum undergoes massive intracellular replication in the reticuloendothelial cells and then disseminates via lymphatic and hematogenous routes. 15• 91 A clinically apparent infection is produced, involving the lungs, liver, lymph nodes, spleen, and eye.* The most prominent feature of infection with Histoplasma is that the pathogen causes massive proliferation of reticuloendothelial tissue within these organs. 92 Cats are as likely as dogs to develop clinical disease. 14• 92 In a retrospective study of 571 cats with systemic mycoses, histoplasmosis was the second most commonly reported fungal infection and was present in 96 animals (17%). 18 The disease seems to be more prevalent in young cats, and, in one study, the mean age of infection was 3.9 years. 18 In that study, Persian cats were slightly overrepresented, and Siamese cats were slightly underrepresented. 18 Most studies report no gender-related predilection for the disease. As is true in other systemic mycotic diseases, immunosuppressive factors have a minor role in predisposing cats to infection with histoplasmosis. Davies and Troy' 8 found that 22 of 96 animals with histoplasmosis had concurrent disease. Fifteen of the concurrent infections were caused by FeLV, two were caused by FIV, and one was caused by feline infectious peritonitis virus (FIPV). 18 There has been no reported predisposition to or exacerbation of disseminated histoplasmosis as a result of systemic corticosteroid administration. 15 Clinical Signs Systemic

Because of the broad spectrum of organ involvement, cats with disseminated histoplasmosis exhibit many nonspecific clinical signs. Typically, these signs have insidious onsets and consist of depression, anorexia, weight loss, fever, and anemia. 15• 91• 92 These nonspecific signs were reported in 67% of 96 affected cats. 18 Respiratory disease was less commonly seen but was reported in 39% of cats with disseminated disease. 18 Pulmonary involvement may be evident radiographically by the presence of focal or miliary densities. 18• 92 Skeletal infection is less common and was seen in 18% of affected cats. 18 Other infrequently reported signs include skin nodules, oral ulcers, and diarrhea. 15 Enlargement of the lymph *References 10, 14, 15, 18, 26, 31, 34, 50, 67, 71, 77, 91, and 92.

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nodes, liver, and spleen may occur. Bone marrow invasion by H. capsulatum may lead to aplastic anemia and pancytopenia. 26 Ocular

Ocular involvement may be more common in disseminated histoplasmosis than in other systemic mycoses of cats. In the retrospective study by Davies and Troy/ 8 24% of 96 cats with histoplasmosis had ocular lesions, whereas in another study of 20 affected cats, all 4 animals that had ophthalmic examinations had ocular involvement. 91 In most of the cases reported in the literature, cats were examined for nonspecific clinical signs, and ocular lesions were discovered secondarily.''· 71 Reported ocular signs include mucoid ocular discharge, blepharospasm, conjunctivitis, chemosis, chorioretinitis, retinal detachment, and secondary glaucoma.15·50·91 The most commonly described lesion is granulomatous chorioretinitis."· 71· 74 Peiffer and Belkin71 described a cat that had bilateral conjunctival hyperemia, aqueous flare, posterior synechiae, iris neovascularization, and nodules on the iridial surface. Fundic examination revealed that the nontapetal area was infiltrated with multiple fluffy exudates, and large granulomas appeared in the tapetal area. 71 In addition, there was optic neuritis, and the optic disks were enlarged, elevated, and edematous. 71 Granulomas were found throughout all major body systems at necropsy. 71 Inflammation extended throughout the eye and into the meninges, consisting of histoplasma-laden macrophages and lymphocytes.71 Diagnostics

Disseminated histoplasmosis can be difficult to diagnose because the presenting signs are nonspecific and can point to diseases of most organ systems. Any cat presenting with fever, anorexia, and weight loss should be suspected of having histoplasmosis. Cats with anterior uveitis or chorioretinitis should also be suspected of having histoplasmosis. Routine hemograms and serum biochemical profiles usually show nonspecific changes, such as anemia and elevated liver enzymes, but, occasionally, the fungal organism may be found in circulating leukocytes. The most reliable way to diagnose histoplasmosis is by isolating the organism from tissue biopsies, impression smears of lesions, lymph nodes aspirates, bone marrow aspirates, pleural or peritoneal fluids, or tracheal washes. 91· 92 Vitreal aspirates are likely to yield H. capsulatum organisms in cats with chorioretinitis because the fungus is numerous in the vitreous, choroid, and retina of infected eyes examined histologically?' Intradermal skin testing (the histoplasmin test done in humans) is unreliable in cats, and serologic tests for antibodies against Histoplasma antigen are usually false-negative. 92 Therapy

As is true in other systemic mycotic diseases with ocular involvement, the systemic disease and the eye must be treated. Systemic antifungal drug treatment and nonspecific ocular treatment are discussed in the section on cryptococcosis. Amphotericin B and ketoconazole have been used to treat histoplasmosis successfully. 67• 83 The highest reported success rate has been with itraconazole. 34 In a prospective study of eight cats, all were eventually cured with itraconazole

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therapy (5 mg/kg per os twice daily), but two cats had recurrences and required 2 to 3 additional months of therapy. 34 One of the cats in which the disease recurred had recurrence of ocular lesions. The itraconazole was administered to that cat for 120 days, and the left eye was enucleated as adjunct therapy after the first 60 days of treatment-34

BLASTOMYCOSIS Pathogenesis

Blastomycosis is caused by the dimorphic fungus Blastomyces dermatitidis. It is principally found in North America but has been reported in Africa and Central America. 41· 48 In the United States, the fungus is found mainly in the Mississippi, Missouri, and Ohio river valleys and the mid-Atlantic states. 48 Humans and dogs are most commonly affected, but blastomycosis also has been reported in cats, horses, sea lions, lions, ferrets, deer, and polar bears. 40· 48• 63 Blastomyces dermatitidis is saphrophytic and lives in soil that is moist, acidic, and rich in decaying vegetation. 63 It has been isolated from bat and pigeon feces. 63• 78 Moist conditions, such as rain or fog, help liberate and aerosolize the fungal conidia that are inhaled by the hosf.3· 63 Within host tissues, the fungus transfers to a spherical, unicellular, budding yeast from 5 to 20 1!.. in diameter surrounded by a double-contoured cell wallY· 48· 63 Relatively uncommon in cats, blastomycosis was found in 41 of 571 cases of feline systemic mycoses. 18 The reasons underlying the lower incidence of the disease in cats than in dogs are unknown. Cats may be less susceptible, may have a lower exposure rate, or may be relatively underdiagnosed with blastomycosis.9 Infection occurs in cats primarily by the inhalation of aerosols containing infective spores.9· 19· 41· 63 The spores enter the terminal airways and establish a primary infection in the lungs. From there, the yeast can disseminate via the blood or lymphatic system to other organs, primarily the central nervous system, skin, and eye. 63 In affected organs, including the eye, B. dermatitidis causes severe pyogranulomatous inflammatory lesions. 1· 48 Cytologically, these consist of macrophages, neutrophils, lymphocytes, and giant cells. The fungus may be found within phagocytic cells or free within tissues or body fluids. 1· 48· 63• 65 Inoculation from the soil into a wound may occasionally lead to localized and perhaps disseminated disease. 48 When three experimental cats were placed on soil infected with B. dermatitidis, all three developed a pulmonary infection within 3 weeks, but there was no dissemination to other organs. 19 Why dissemination occurs in some cats but not in others is unknown. Immunosuppression does not seem to have a major role in predisposition to or dissemination of blastomycosis. Most cats described in published clinical reports have been serologically negative for FeLV, FIP, or FIV. 18· 63 Sex, age, and breed may have a role in predisposing cats to the disease. In a retrospective study of 22 cats, 75% were 4 years of age or younger, and males comprised 70% of the cases. 63 Other studies have found that sex and age are not major predisposing factors. 9 Miller and co-workers 63 found a predisposition in Siamese and Siamese-mix cats, which accounted for 9 of 20 cases in which breed was reported. Four of these nine Siamese cats had been purchased at the same pet shop. 18· 63

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Clinical Signs Systemic

Blastomycosis in cats may present with a wide variety of clinical signs. It may present as a localized disease such as a draining skin wound or paronychial infection (perhaps owing to local inoculation of the organism) or as a localized pulmonary infection. 63 More commonly, the fungus disseminates, and multiple organ systems become involved. The most commonly reported respiratory signs are dyspnea and cough. Fifty-one percent of the 41 cases of feline blastomycosis reported by Davies and Troy18 had clinical signs of respiratory disease. Thoracic radiographs of affected cats typically show a mixed pulmonary pattern consisting of interstitial, bronchial, and peribronchial disease. 48, 66 Nonspecific clinical signs of anorexia, weight loss, and lethargy were present in 54% of the 41 just mentioned cases, and central nervous system involvement was reported in 41% of 22 of the cases in the literature reviewed by Davies and Troy. 18 Central nervous system signs included cerebral blindness, hyperesthesia, proprioceptive deficits, extensor rigidity, upper motor neuron signs, and lateral recumbency. 1' 9, 48' 63 The cutaneous system was involved in 23% of the 22 cats. 18 Cutaneous lesions are typically subcutaneous pyogranulomas, abscesses, or draining fistulas. 48' 63, 66 These lesions may be found in conjunction with disseminated disease or alone. Bony involvement is rarely reported in cats, although it is commonly seen in dogs with blastomycosis. 18, 63 Ocular

The eye is frequently involved in feline disseminated blastomycosis. The fungus generally causes a severe pyogranulomatous uveitis. 1' 48' 63' 65 One or both eyes may be involved.", 65 Of 22 cats with disseminated blastomycosis, 4 (18%) had ocular involvement. 18 Clinical ocular signs may include blindness, chorioretinitis, and anterior uveitis.'' 9, 18, 63, 65, 66 Miller and co-workers 63 described two cats with ocular blastomycosis that had similar clinical signs. These signs were unilateral and consisted of blindness, severe aqueous flare, posterior synechiae, keratic precipitates, rubiosis iridis (reddening of the irides), severe retinal detachments with subretinal pyogranulomas, and intraretinal pyogranulomas. 63 Nasisse and co-workers65 described a cat in which large areas of diffuse chorioretinitis affected primarily the tapetal area. Miller and colleagues63 reported that all cats in their retrospective study had more severe involvement of the posterior segment of the eye compared with the anterior segment. This pattern of involvement is also seen in dogs.U Blindness in cats with blastomycosis can also be caused by central nervous system lesions while the eye remains unaffected. 63 Diagnostics

Blastomycosis may be difficult to diagnose in cats because it often presents with nonspecific clinical signs. Of 41 cats studied by Davies and Troy, 18 68% were diagnosed only at necropsy. Blastomycosis should be considered as a possible cause of any respiratory disease of cats and should be suspected in cats with draining skin lesions and central nervous system signs. 18, 48 Definitive diagnosis is almost always based on cytologic or cultural identifi-

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cation of B. dermatitidis because serologic testing is unreliable in cats. 48• 63 Aspirates of enlarged lymph nodes and impression smears of skin nodules or draining exudate will yield organisms in the majority of cases. 48 When the disease is primarily ocular, if less invasive measures fail to demonstrate the organism, it can often be retrieved from vitreous or subretinal aspirates12· 48 or demonstrated on histopathology of an enucleated eye. 48 Aqueous aspirates are unlikely to demonstrate the organism because it is rarely found in the anterior segment in enucleated eyes. 12· 63 Therapy

Few cases are reported in the literature regarding the treatment of cats with blastomycosis. Of 22 cases in the retrospective study by Davies and Troy, 18 only 7 were treated. Four of these cats responded, and three died or were euthanized.18 Miller and co-workers 63 reported that two of the three cases of systemic blastomycosis that they treated (included in the study by Davies and Troy) responded to combined therapy with amphotericin B and ketoconazole and were alive and asymptomatic for at least 19 months. Both of these cats had ocular lesions. In one cat, the affected eye was enucleated; in the other cat, the ocular granulomas disappeared, and only retinal detachment owing to traction band formation remained. 63 Legendre48 recommended the use of itraconazole, 5 mg/kg twice daily, as an effective treatment for most cats with blastomycosis. COCCIDIOIDOMYCOSIS Pathogenesis

Coccidioidomycosis occurs in the southwestern United States, Central America, and parts of South America. 28 Although coccidioidomycosis is common in dogs, cats may be less susceptible or perhaps have not been adequately examined for the disease. 28 In a retrospective study of 571 cases of deep mycoses in cats, 53 had coccidioidomycosis. 18 Forty-eight of these 53 cases were described in greater detail by Greene and Troy.Z8 Only five cases of feline coccidioidomycosis had been reported in the veterinary literature before 1995. 2· 75· 79· 90 In their retrospective study, Greene and Troy found that 41 of the 48 cases had been diagnosed with coccioidiomycosis during a recent 3-year period/8 suggesting an increase in the incidence of the disease in cats or an improvement in diagnostic abilities. 28 No breed or sex-related predilection for the disease is known. 18· 29· 81 In the study by Greene and Troy, the mean age of cats at diagnosis of the infection was 6.2 years (median, 5 years ). 18· 28 Coccidioidomycosis is caused by Coccidioides immitis, a large thick-walled dimorphic fungus. C. immitis produces mycelial colonies with arthrospores in the soil but produces endospore-forming spherules in animal tissue.42 These spherules range from 10 to 80 IJ..m in diameter. 2· 29 C. immitis is a saprophyte in the soil and infects the host through inhalation of arthrospores or by direct inoculation into wounds. 42 Systemic dissemination results from hematogenous spread, usually from the lungs. C. immitis reproduces in tissues by the formation of endospores, which fill the parent organism and rupture it, thus spreading the organism within the body of the cat. As is true in cryptococcosis, histoplasmosis, and blastomycosis, immunosuppressive diseases do not seem to predispose cats to coccidioidomycosis.29

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Clinical Signs Systemic In cats, coccidioidomycosis usually involves the skin, respiratory system, musculoskeletal system, central nervous system, or eye. 28 Of 48 cases reviewed, 56% had cutaneous lesions, 25% had respiratory signs, 19% had neurologic lesions, and 19% had musculoskeletal signs. In another study, 44% of cases had nonspecific clinical signs of weight loss, anorexia, and fever. 18 Cutaneous lesions were abscesses that resisted routine therapy, 89 draining skin lesions/9 subcutaneous granulomatous masses, and localized lymphadenopathy. 29 Respiratory signs consisted of respiratory difficulty and hilar lymphadenopathy. 29 Thoracic radiographs were not obtained in most of the cases owing to the infrequency of respiratory signs. Lameness was seen in some cats and was attributed to softtissue and bony lesions. Radiographically, the bony lesions were lytic and proliferative. Neurologic and ocular abnormalities occurred in 19% of the cats. Clinical signs of neurologic abnormalities consisted of hyperesthesia, posterior paresis, seizures, and incoordination.

Ocular

Only one case report of ocular coccidioidomycosis was found in the pre1995literature.Z Greene and Troy found that 6 (13%) of 48 cats in their retrospective study had ocular lesions. 28 These six cats had retinal detachments and uveitis/iritis. Angell and co-workers2 described a cat presented for evaluation of a "reddish hue" in one eye. A fibrin clot that restricted examination of the fundus was found in the anterior chamber of the eye. As the fibrin decreased, a mass became visible in the anterior chamber. The eye was enucleated, and histopathologic examination showed a chronic pyogranulomatous endopththalmitis and ruptured lens capsule. C. immitis spherules were present throughout the uveal tract. Interestingly, there were no other clinical signs attributable to coccidioidomycosis in this cat, and there was no evident recurrence 2 years after the surgery. Because there was no evidence of keratitis or regional lymphadenopathy, Angell and colleagues concluded that the eye had been infected hematogenously rather than by direct penetration of the globe. Diagnostics

Coccidioidomycosis can be diagnosed by cytologic demonstration of C. immitis from cutaneous lesions and tracheal washes, by histologic evaluation of biopsy specimens, by culturing the organism, or by serologic testing. 29 Of the 48 cases that were reviewed by Greene and Troy, 28 39 were tested for antibodies against C. immitis, and all of these cats were positive at some time during the course of their disease. Twenty-nine (82%) had positive precipitin antibodies on initial testing. 2 Precipitin antibodies are thought to be immunoglobulin M, are detectable within 2 to 4 weeks after infection/9• 70 and may persist up to 1 year.'0 Complement-fixing antibodies were present in all 39 cats on which serology was performed, including the 10 cats that had negative precipitin antibody titers. 28 Complement-fixing titers ranged from 1:2 to 1:128, with most cats having titers of 1:16 or greater. 28 Precipitin antibody and complement-fixing titers remained elevated in cats even after therapy was initiated and maintained/8 thus monitor-

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ing antibody titers in cats is probably not a good way to track progression of the disease or the response to therapy. Therapy

As is true in other systemic mycotic diseases with ocular involvement, the systemic disease and the eye must be treated. Systemic antifungal drug treatment and nonspecific ocular treatments are discussed in the section on cryptococcosis. Among the 48 cats with coccidioidomycosis reported on by Greene and Troy, 28 treatment was attempted in 44. The average duration of antifungal treatment was 10 months, with treatment in some cats continued for up to 43 months. 28 Although most of these cats were treated with ketoconazole, the treatment regimen recommended by Malik and co-workers54 (itraconazole or fluconazole) for cryptococcosis may be more effective for the treatment of coccidioidomycosis. OTHER FUNGAL INFECTIONS

Although cats are susceptible to several other systemic fungal diseases, ocular symptoms have been reported in only a few of these diseases. Systemic aspergillosis was reported in 40 of 571 cats with deep mycoses. 18 Clinical signs associated with this disease were lethargy, depression, vomiting, and diarrhea. A high incidence of concurrent disease was present in cases with disseminated aspergillosis (unlike in other systemic mycoses), indicating that immunosuppression may have a role in predisposing cats to this disease. 18 One case report of a cat with aspergillosis has described ocular signs. 89 That cat was presented for evaluation of bilateral proptosis of the globes and prolapsed nictitating membranes. Both eyes showed conjunctival hyperemia and blood-tinged ocular discharge. Elevated intraocular pressures and cupping of the optic disks indicated a secondary glaucoma. After glaucoma therapy, the eyes improved, but the exophthalmos remained. A mass was located in the orbit, and the cat was euthanatized. Large numbers of branching septate fungal hyphae, typical of Aspergillus, were found in the orbit. The fungus may have arrived in the orbit by dissemination from the lungs or by local extension through the nasal passages and sinuses. 89 A similar case with orbital cellulitis (leading to severe exophthalmos), sinusitis, and pneumonitis caused by Penicillium was reported by Peiffer and coworkers.72 In that case, the organism was thought to have gained entry to the orbit via extension from the sinuses. Candida albicans is a normal inhabitant of the alimentary, nasal, and genital mucosa. It may act as an opportunistic pathogen and infect locally and can also disseminate in immunocompromised animals. Nine cats have been reported to have disseminated candidiasis. 18 Four of these animals had intestinal involvement, one had pyothorax, and two had ocular disease. 18• 27• 62 One of the cats with ocular disease presented with neurologic signs of ataxia, head tilt, and circling.62 He also was emaciated and dehydrated. Ocular signs consisted of decreased menace, palpebral and oculocephalic reflexes, and horizontal nystagmus. Bilateral chemosis, corneal edema, and miosis were present. Marked anterior and posterior uveitis was present in both eyes as indicated by keratic precipitate, aqueous flare, fibrin clots in the anterior chambers, and gray-towhite nodules in all regions of the fundus. Diagnosis of the disease was based on vitreal aspirates containing yeastlike organisms 3 to 5 J-Lm in diameter that

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were later identified as C. albicans. Necropsy revealed white firm nodules in most organs and infiltration of the retina with inflammatory cells and Candida organisms. The other cat with ocular lesions was initially presented for evaluation of a corneal ulcer from which C. albicans was isolated. 27 Later, the cat developed systemic candidiasis and had severe panuveitis.

SUMMARY

Systemic fungal diseases are important diagnostic considerations in all sick cats, particularly in cats with ocular symptoms. The most common ocular manifestation of these diseases is posterior uveitis (choroiditis); however, anterior uveitis is sometimes present and is usually secondary to the inflammation in the posterior segment. Occasionally, adnexal diseases such as blepharitis, inflammation of the nictitating membrane, and ocular discharge may be present in cats with systemic mycoses. The prognosis for cats with systemic fungal diseases has changed with the advent of the triazole antifungal drugs. In the past, the prognosis was guarded to poor for survival of the cat. Today; with prolonged antifungal therapy; many cats recover completely from their disease. The prognosis for return of vision for eyes affected with systemic fungal disease is still guarded. Often, even if the infection is controlled systemically, the retina is severely damaged and may remain nonfunctional.

References 1. Alden CL, Mohan R: Ocular blastomycosis in a cat. J Am Vet Med Assoc 164:527528, 1974 2. Angell JA, Shively JN, Merideth RE: Ocular coccidioidomycosis in a cat. J Am Vet Med Assoc 187:167-169, 1985 3. Archer JR, Trainer DO, Schell RF: Epidemiologic study of canine blastomycosis in Wisconsin. JAm Vet Med Assoc 190:1292-1295, 1987 4. Aronson E, Bendickson JC, Miles KG, et al: Disseminated histoplasmosis with osseous lesions in a cat with feline lymphosarcoma. Vet Radiol 27:50-53, 1986 5. Barrett RE, Scott DW: Treatment of feline cryptococcosis: Literature review and case report. JAm Anim Hosp Assoc 11:511-518, 1975 6. Blouin P: Experimental feline cryptococcosis: Characteristics and pathogenesis of ocular lesions [thesis]. University of California (Davis), 1979 7. Blouin P, Cello RM: Experimental ocular cryptococcosis: Preliminary studies in cats and mice. Invest Ophthalmol Vis Sci 19:21-30, 1980 8. Blouin P, Conner MW: Cryptococcosis (torulosis, European blastomycosis) In Holzworth J (ed): Diseases of the Cat, Medicine and Surgery. Philadelphia, WB Saunders, 1987, pp 332-342 9. Breider MA, Walker TL, Legendre AM: Blastomycosis in cats: Five cases (1979-1986). J Am Vet Med Assoc 193:570-572, 1988 10. Breitschwerdt EB, Halliwell WH, Burk RL, et al: Feline histoplasmosis. J Am Anim Hosp Assoc 13:216-222, 1977 11. Brooks DE, Legendre AM, Gum GG: Treatment of canine ocular blastomycosis with systemically administered itraconazole. Progress in Veterinary and Comparative Ophthalmology 1:263-268, 1991 12. Buyukmihci NC, Moore PF: Microscopic lesions of spontaneous ocular blastomycosis in dogs. J Comp Pathol97:321-328, 1987 13. Clark L, Roubin GS: Cryptococcosis in a cat. Aust Vet J 46:544-548, 1970

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14. Oinkenbeard KD, Cowell RL, Tyler RD: Disseminated histoplasmosis in cats: 12 cases (1981-1986). JAm Vet Med Assoc 190:1445--1448, 1987 15. Clinkenbeard KD, Wolf AM, Cowell RL, et al: Feline disseminated histoplasmosis. Comp Vet Med Pract Vet 11:1223-1235, 1989 16. Como JA, Dismukes WE: Oral azole drugs as systemic antifungal therapy. N Eng! J Med 330:263-272, 1994 17. Curtis AJ: A case of torulosis in a domestic cat. Aust J Med Tech 1:71, 1951 18. Davies C Troy GC: Deep mycotic infections in cats. J Am Anim Hosp Assoc 32:380391, 1996 19. Denton JR, DiSalvo AF: Respiratory infection of laboratory animals with conidia of Blastomyces dermatitidis. Mycopathol Mycol Appl 36:129-136, 1968 20. Dye JA, Campbell KL: Cutaneous and ocular cryptococcosis in a cat: Case report and literature review. Comp Anim Pract 2:34-42, 1988 21. Emms SG: Ketoconazole in the treatment of cryptococcois in cats. Australian Veterinary Journal 64:276-277, 1987 22. Emmons CW: Saprophytic sources of Cryptococcus neoformans associated with the pigeon (Columba Iivia). Am J Hygiene 62:227-232, 1955 23. English RV: Immune responses and the eye. In Gelatt KN (ed): Veterinary Ophthalmology, ed 3. Baltimore, Lippincott Williams & Wilkins, 1999, pp 239-258 24. Fischer CA: Intraocular cryptococcosis in two cats. JAm Vet Med Assoc 158:191-198, 1971 25. Flatland B, Greene RT, Lappin MR: Clinical and serologic evaluation of cats with cryptococcosis. JAm Vet Med Assoc 209:1110-1113, 1996 26. Gabbert NH, Campbell TW, Beiermann RL: Pancytopenia associated with disseminated histoplasmosis in a cat. JAm Anim Hosp Assoc 20:119-122, 1984 27. Gerding PA, Morton LD, Dye JA: Ocular and disseminated candidiasis in an immunosuppressed cat. JAm Vet Med Assoc 204:1635-1638, 1994 28. Greene RT, Troy GC: Coccidioidomycosis in 48 cats: A retrospective study (1984--1993). J Vet Intern Med 9:86-91, 1995 29. Greene RT: Coccidioidomycosis. In Greene CE (ed): Infectious Diseases of the Dog and Cat, ed 2. Philadelphia, WB Saunders, 1998, pp 391-398 30. Gwin RM, Gelatt KN, Hardy R, et al: Ocular cryptococcosis in a cat. J Am Anim Hosp Assoc 13:680-684, 1977 31. Gwin RM, Makley TA, Wyman M, et a!: Multifocal ocular histoplasmosis in a dog and cat. JAm Vet Med Assoc 176:638-342, 1980 32. Halliday CL, Bui T, Krockenberger M, et al: Presence of and mating types in environmental and clinical collections of Cryptococcus neoformas var. gati from Australia. J Clin Microbiol, in press 33. Hansen BL: Successful treatment of severe feline cryptococcosis with long-term high doses of ketoconazole. JAm Anim Hosp Assoc 23:193-196, 1987 34. Hodges RD, Legendre AM, Adams LG, et a!: Itraconazole for the treatment of histoplasmosis in cats. J Vet Intern Med 8:409-413, 1994 35. Holzworth J: Cryptococcosis in a cat. Cornell Veterinarian 42:12-15, 1952 36. Holzworth J, Coffin DL: Cryptococcosis in the cat: A second case. Cornell Vet 43:546554, 1953 37. Howlett CR, Duff BC, Allan GS: Systemic cryptococcosis in a cat. Aust Vet J 49:535538, 1973 38. Jacobs GJ, Medleau L, Calvert C, eta!: Cryptococcal infection in cats: Factors influencing treatment outcome, and results of sequential serum antigen titers in 35 cats. J Vet Intern Med 11:1-4, 1997 39. Jacobs GJ, Medleau L: Cryptococcosis. In Greene CE (ed): Infectious Diseases of the Dog and Cat, ed 2. Philadelphia, WB Saunders, 1998, p 383 40. Jasmin AM, Carroll JM, Baucom MT: Systemic blastomycosis in Siamese cats. Vet Med Small Anim Oin 64:33-37, 1969 41. Kwon-Chung KJ, Bennett JE: Blastomycosis In Kwon-Chung KJ, Bennett JE (eds): Medical Mycology. Philadelphia, Lea and Febiger, 1992, pp 248-279 42. Kwon-Chung KJ, Bennett JE: Coccidioidomycosis. In Kwon-Chung KJ, Bennett JE (eds): Medical Mycology. Philadelphia, Lea and Febiger, 1992, pp 356-396

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JE: Cryptococcosis. In Kwon-Chung KJ, Bennett JE (eds): Medical Mycology. Philadelphia, Lea and Febiger, 1992, pp 397-446 44. Kwon-Chung KJ, Bennett JE: Hisoplasmosis. In Kwon-Chung KJ, Bennett JE (eds): Medical Mycology. Philadelphia, Lea and Febiger, 1992, pp 464-513 45. Lau RE, Reinke JD, Brown SG: Cryptococcosis in a cat. Vet Med Small Anim Clin 66: 43. Kwon-Chung KJ, Bennett

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Address reprint requests to Juliet R. Gionfriddo, DVM, MS Department of Clinical Sciences Colorado State University College of Veterinary Medicine Fort Collins, CO 80523