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Cryptococcosis

Issue Description
Infection occurs by inhalation of the fungus from its natural soil habitat. Once inhaled in the lungs, they multiply and may disseminate through the blood and lymphatics to other organs, including the skin, bone, genitourinary tract, and brain. The incubation period is 30 to 100 days, although infection can be asymptomatic.


Symptoms
The four groups of organs affected are the respiratory tract, central nervous system, eyes, and skin. The clinical signs, therefore, depend on the system(s) affected. Respiratory infections (seen in > 80% of cases) are characterized by sneezing, nasal discharge (pus-filled, bloody, or clear), swelling underneath the skin in the nasal area, mouth lesions, and swelling of lymph nodes. Neurological signs vary with the location of the lesion and can include depression, poor movement coordination, seizures, partial paralysis, and blindness. Eye abnormalities predominately affect the retina, choroid, and optic nerve. Clinical signs can range from dilated, unresponsive pupils and blindness to chorioretinitis, anterior uveitis, and retinal damage. 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.

Skin 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 spreading of the infection to the skin. A more rare presentation of cryptococcosis may include bone destruction, chronic cough, and kidney failure.

Dogs are infected by C. neoformans much less frequently than cats (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. The clinical signs are similar to those found in cats except that fever (103-105° F) is seen more often in affected dogs.


Treatment
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.

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. Malik et al. have devised a new subcutaneous infusion method of administering AMB which is less toxic and less expensive. 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.

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.

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 blood-brain barrier well.

Fluconazole (FCZ) is another triazole agent that does have the ability to cross the blood-brain barrier 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.

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).


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