Canine and Feline Cryptococcosis

Cecily A. Reynolds, DVM; Perry J. Bain, DVM, PhD; and Kenneth S. Latimer, DVM, PhD

Class of 2003 (Reynolds), Department of Pathology (Bain, Latimer), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388

Introduction

Cryptococcosis is caused by a Gram-positive yeast that has worldwide distribution with an increased incidence in temperate regions such as southern California and Australia. It affects numerous mammalian species, including dogs, cats, and humans. Cryptococcus neoformans is the species that primarily causes this disease in domestic pets.1 C neoformans is a saprophytic, round to oval, yeast-like fungus measuring 3.5-7.0 microns in diameter. It also has a characteristic "soap-bubble" appearance due to the large heteropolysaccharide capsule that protects the organism from desiccation when invading tissues.2

Two variants, Cryptococcus neoformans var. neoformans and gattii, and five serotypes (A, B, C, D, AD) have been identified.1 Several sources of C. neoformans exist, including bird (especially pigeon) excreta which contain high amounts of nitrogen-containing compounds such as creatinine, soil and fruits. Cryptococcus sp. can survive in feces for up to two years, unless viability is reduced by dry conditions or UV light. It does not spread via direct contact but instead is transmitted by inhalation of the aerosolized organism from the soil or feces.2 Cryptococcus neoformans var. gattii is primarily found in tropic and subtropic areas due to its very specific habitat of Eucalyptus trees.3

Life Cycle

Cryptococcal reproduction occurs by the formation of blastoconidia, which are buds connected by a narrow isthmus to the parent cell.4 Cryptococcus neoformans differs from other dimorphic fungi in that it is always found in the yeast phase in laboratory cultures and infected tissues. Inhalation of the aerosolized organism is the most probable source of infection; however, the exact mode of transmission is unknown. The organism can deposit in the upper or lower respiratory tract. However, the organism primarily remains in the upper airways since the encapsulated organisms (5-20 micrometers in diameter) are larger than the diameter of the terminal airways. This leads to a predominance of upper respiratory infections rather than pulmonary disease. Once established in the airways, the infection can spread hematogenously or by tissue invasion through the cribiform plate to the brain.2 Mammals with normal immune systems usually clear the cryptococcal infection prior to its spread. The majority of resistance is provided by cell-mediated immunity. Infections with Cryptococcus neoformans may indicate immunosuppression in cats with FIV and FeLV, dogs with Ehrlichiosis or chronic glucocorticoid therapy, and humans with HIV/AIDS, Hodgkin’s disease, or sarcoidosis.5

Clinical Signs and Physical Findings

Cryptococcosis is the most common fungal disease in cats and should be an important differential diagnosis when a cat presents with sneezing and nasal discharge that is unresponsive to antibiotics.6 The age range of infected cats varies widely (1-13 yrs), with a mean age of 5 years. There is a predilection for infection in male cats, most likely due to the increased roaming of toms. Siamese cats are also overrepresented in most studies. Outdoor cats also have an increased predominance of cryptococcosis as compared with indoor cats. However, keeping cats indoors does not prevent them from contracting the disease. Potting soil in house plants and moldy, unfinished basements may be sources of infection in indoor cats.5

The four primary systems affected are the respiratory, central nervous, ocular, and cutaneous systems. The clinical signs, therefore, depend on the system(s) affected.1 Respiratory infections (seen in >80% of cases) are characterized by sneezing, nasal discharge (mucopurulent, hemorrhagic, or serous), subcutaneous swelling over the nasal planum and bridge, oral lesions, submandibular lymphadenopathy, and destruction of the nasal turbinates.2

Neurological signs vary with the locale of the lesion and can include depression, ataxia, seizures, paresis, and blindness.2

Ocular abnormalities predominately affect the retina, choroid, and optic nerve. Eye infections can arise hematogenously or via extension from the brain by the optic nerve. Clinical presentation can range from dilated, unresponsive pupils and blindness to chorioretinitis, anterior uveitis, and retinal damage.4 While the prognosis for survival with the ocular form of Cryptococcus is fair to good using triazole antifungals, the prognosis for return of vision is guarded to poor due to retinal damage.7

Dermal lesions are seen in approximately 45% of infected animals and often occur with additional organs simultaneously being affected. The skin lesions are more likely caused by previous dissemination rather than infection by direct trauma to the skin. A more rare presentation of cryptococcosis may include anorexia, peripheral lymphadenopathy, bone lysis, chronic cough, and renal failure.1

Dogs are not infected by C. neoformans nearly as often as their feline counterparts. The prevalence in dogs is .00013%, as compared to cats that are 7-10 times more likely to be infected. The average age of infected dogs is 3.5 years and, unlike cats, there is no gender predisposition. Overrepresented dog breeds include American Cocker Spaniels and Labrador Retrievers in North America, and Doberman Pinschers and Great Danes in Australia. Cryptococcosis affects the same four organ systems as with cats, but the CNS and eyes are more commonly involved in dogs than in cats.1 The clinical signs are similar to those found in cats except that fever (103-105° F) is seen more often in affected dogs (25% of cases).8

Laboratory and Other Findings

Additional clinical findings, other than those observed on physical examination, are rare. Endoscopy (specifically rhinoscopy), cannot provide clear evidence of a fungal infection and is more beneficial for biopsies of the swollen nasal dorsum or granulomas, as opposed to visualization of the infected tissue. The thick, mucinous nasal material can also be obtained using an otoscope speculum.8

Cryptococcus neoformans also differs from most other mycotic agents in that radiographs rarely aid in diagnosis. Moth-eaten nasal turbinates with an osteolytic appearance are rarely seen because C. neoformans is usually nondestructive. More commonly, a fluid opacity in the nasal passages and frontal sinuses is seen with surrounding soft-tissue swelling. Chest radiographs are almost always normal, although occasional small nodular lesions may be seen in addition to a secondary bronchopneumonia.8

Gross pathologic findings may range from a gelatinous mass (with several organisms and low numbers of inflammatory cells) to granulomas. An influx of macrophages, giant cells, and some plasma cells and lymphocytes often surrounds the encapsulated organisms, and these cells may be seen with cytologic or histopathologic examination of lesions. Complete blood counts on infected animals may show mild anemia, eosinophilia, and monocytosis. Serum biochemical test results are usually within reference intervals.

Diagnosis

The most rapid and practical means of diagnosing Cryptococcus neoformans is by cytological evaluation of nasal exudates, tissue aspirates, urine, or CSF using one of many stains (Figure 1). Wright’s stain can be used; however, the methyl alcohol can dehydrate and distort the characteristic capsule. Additional diagnostic stains include new methylene blue, Gram stain, and India ink. Caution must also be exercised when examining India ink preparations to prevent confusing lymphocytes, fat droplets, or aggregated ink particles with the organisms.6

Figure 1. Cryptococcus neoformans in nasal exudate from a cat (Wright’s stain). Note the thick, non-staining capsule. The arrow indicates a budding organism.

A negative cytological examination does not exclude cryptococcosis. The next logical choice for diagnostic testing is latex agglutination which detects the cryptococcal capsular antigen of all known serotypes found in serum, urine, or CSF.8 Commercial kits are very reliable and have 90-100% sensitivity and 97-100% specificity. The specificity is highest when the serum is pretreated with a protease (pronase).1 The latex agglutination test is useful for diagnostic purposes and also for monitoring response to treatment. Effective therapies should cause the initial titer to decrease to 10% or less within 2 months of drug administration.5

Definitive diagnosis can also be determined via examination of tissue biopsies and fungal cultures. Histologically, the organism can be stained with hematoxylin and eosin, periodic acid-Schiff, Gomori's methenamine silver, Masson-Fontana, or Mayer’s mucicarmine techniques; the latter staining technique is considered definitive. C. neoformans has a thick capsule, thin cell wall, budding, and lack of endospores which differentiate it from Blastomycoides sp. and Coccidiodes sp. Cryptococcus neoformans can be cultured from exudates, spinal fluid, urine, joint fluid, and tissue samples on Sabouraud’s agar with antibiotics at 25-37°C.1

Figure 2. Section of lung from a cat with cryptococcisis. Numerous, variably-sized yeasts are present in a terminal airway (hematoxylin and eosin stain).

Treatment and Prevention

Note: Treatment of animals should only be performed by a licensed veterinarian. Veterinarians should consult a veterinary internist, the current literature, and current pharmacological formularies before initiating any treatment protocol.

Some veterinary surgeons advocate debulking any large, protruding, fungal masses for palliative relief of difficult breathing (stridor or dyspnea). However, this surgery will not cure the infection and is highly invasive. Long-term administration of antifungal drugs is the crux of therapy and the rhinotomy is not necessary. The current drugs used to treat cryptococcosis are the polyenes, azoles, and flucytosine.6

Amphotericin B (AMB), alone or in combination with other antifungal drugs, has been previously used to treat cryptococcosis. However, this drug is usually reserved for life-threatening and previously unresponsive cases due to its toxicity. Several disadvantages of AMB make it less desirable than other drugs. Intravenous treatment is difficult and causes many adverse reactions, AMB has side-effects including nephrotoxicity and severe azotemia, it has poor efficacy in dogs, and is ineffective with cryptococcal meningitis because AMB does not cross the blood-brain barrier (BBB).6 Malik et al. have devised a new subcutaneous infusion method of administering AMB which is less toxic and less expensive.9 New attempts at decreasing toxicity have also involved changing the drug into lipid and lipidsomal-encapsulated formulations. However, these lipid drugs are extremely expensive. The drug flucytosine can also be added to AMB to increase the success of therapy.1

Ketoconazole (KTZ) is another treatment option for cryptococcosis. KTZ is an imidazole derivative that is given orally once daily with food to decrease unwanted side-effects such as anorexia, gastrointestinal upset, and liver disease. Like AMB, KTZ does not cross the BBB and is not as effective in dogs. It should be noted that this decreased efficacy in dogs could be due to the higher prevalence of disseminated and neurologic disease.1

Itraconazole (ITZ) is a triazole antifungal drug similar to KTZ but with fewer adverse side-effects. If gastrointestinal or liver disease is seen, ITZ can be discontinued for 2 weeks and then re-administered at half the original dose. ITZ also does not penetrate the BBB well.5

Fluconazole (FCZ) is another triazole agent that does have the ability to cross the BBB and has fewer side effects than the aforementioned antifungal compounds. FCZ has been reported to have the highest success rates in cats, including those with advanced, longstanding, or disseminated disease. It should be noted that FCZ is only FDA approved for use in humans.4

Outcomes of treatment of cryptococcosis are quite varied. Drug therapy is long-term (average of 8.5 months) and relapses occur frequently. Patients with the CNS form of cryptococcosis will require lifelong treatment maintenance. It is recommended that treatment continue for one month after resolution of clinical signs in combination with decrease in antigen titer by at least two orders of magnitude or until serum cryptococcal antigen is undetectable. The prognosis is much worse if the patient has the neurologic form of disease or is immunocompromised by FeLV or FIV infections.3 Since Cryptococcus neoformans is ubiquitous, the best means of prevention is to decrease contact with areas containing a high concentration of organisms (pigeon droppings, damp buildings or basements).1

References

1. Jacobs GJ, Medleau L: Cryptococcosis. In: Greene CE: Infectious Diseases of the Dog and Cat. WB Saunders, Philadelphia, 1998, pp 383-390.

2. Gerds-Grogan S, Dayrell-Hart B: Feline Cryptococcosis: A retrospective evaluation. J Am Anim Hosp Assoc 33:118-122, 1997.

3. Malik R, Wigney DI, Muir DB, Gregory DJ, Love DN: Cryptococcosis in cats: Clinical and mycological assessment of 29 cases and evaluation of treatment using orally administered fluconazole. J Med Mycol 30: 133-144, 1992.

4. Jubb KVF, Kennedy PC, Palmer N: Pathology of Domestic Animals, 4th ed. Academic Press Inc, San Diego, 1993, pp 488-489.

5. Jacobs GJ, Medleau L, Calvert C, Brown J: Cryptococcal infection in cats: Factors influencing treatment outcome, and results of sequential serum antigen titers in 35 cats. J Vet Int Med 11(1):1-4, 1997.

6. Lappin MR: Management of feline upper respiratory tract infections. North American Veterinary Conference Proceedings, 2000.

7. Giofriddo JR: Feline systemic fungal infections. Vet Clin North Am Small Animal Pract 30:1029-1050, 2000.

8. Legendre AM, Toal RL: Diagnosis and treatment of fungal diseases of the respiratory system. In: Bonagura JD: Kirk’s Current Veterinary Therapy XIII. WB Saunders, Philadelphia, 2000, pp 815-819.

9. Malik R, Craig AJ, Wigney DI, Martin P, Love DN: Combination chemotherapy of canine and feline cryptococcosis using subcutaneously administered amphotericin B. Aust Vet J 73:124-128, 1996.


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