Systemic fungal diseases (Proceedings)

The fungal organisms most commonly associated with systemic disease are Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis and cryptococcosis.

Blastomycosis

Blastomycosis refers to the systemic disease caused by Blastomyces dermatitidis. Blastomycosis is most common in North America along the larger river valleys (Mississippi, Ohio, Missouri) and east coast (mid-Atlantic states) into Canada. This is a dimorphic fungus that exists in the environment in a saprophytic mycelial form. Acidic, sandy soil near water is believed to be the most common source of exposure. The mycelial form reproduces sexually in the environment producing infective spores.

Disease is much more common in the dog than the cat. There is no sex, age or breed predilection in the cat. In the dog being male, younger, large breed, or a sporting breed may be risk factors. The disease does have a seasonal occurrence in some, but not all, regions. These spores are inhaled and become yeasts within the body. These yeasts are then disseminated via vascular or lymphatic routes. More common sites of infection include the lungs, skin, eyes, lymph nodes, bone, brain, and testes. Common clinical signs include fever, anorexia, weight loss, dyspnea, cutaneous nodules, draining tracts, lameness, and ocular lesions.

Bloodwork may reveal a mild normocytic normochromic anemia, moderate luekocytosis, hyperglobulinemia, and hypoalbuminemia due to chronic inflammation and infection. Hypercalcemia is also sometimes seen due to a PTH-independent increase in 1,25 - dihydroxyvitamin D.

Radiographic findings within the thorax include tracheobronchial lymphadenopathy and diffuse nodular interstitial or bronchointerstitial changes. Mass like lesions and effusion are less common. Radiographic changes in bone include osteolysis, periosteal proliferation and soft tissue swelling.

Diagnosis is typically made by identification of the yeast in tissues cytologically (most commonly) or histologically. Cytology is typically done on lymph node or cutaneous aspirates but vitreal taps, bronchial washes, lung aspirates, urinalysis, and csf can be evaluated for organisms. The yeast is ovoid, 5 to 20 µm, single or budding, with a thick refractile wall. Histopatholgy, on tissues suspicious of infection, is performed when cytology is not possible or diagnostic and reveals organisms as well as granulomatous or pyogranulomatous inflammation. Antibody detection via serology is not typically performed. With acute infections dogs may not have detectable titers and, although it appears uncommon, dogs without clinical disease may have antibody titers. There is a blastomyces antigen enzyme immunoassay available for dogs that detects cell wall galactomannan in serum, urine and csf. Unfortunately there is cross reactivity in dogs with blastomycosis and histoplasmosis. In humans there is cross reactivity between histoplasmosis, coccidiomycosis, paracoccidiomycosis, and penicillosis. Utilizing this immunoassay, antigen levels can also be followed during treatment. PCR has been performed on histologic samples but is not as readily available. Culture can be performed but is not typically necessary or recommended.

Itraconazole is used most commonly to treat this disease in dogs and cats. Amphotericin B was utilized historically but itraconazole appears as effective with fewer side effects and less expense. Amphotericin B is recommended when there is severe clinical disease and evidence of CNS involvement. Voriconazole and fluconazole can be used with CNS and ocular involvement. Fluconazole is also recommended when there is urinary tract involvement because of its excretion into urine. Treatment is for a minimum of 90 days and 30 days past resolution of signs. Glucocorticoids have been used short term in severe respiratory infections and when airway obstruction secondary to tracheobronchial lymphadenopathy occurs.

Most dogs treated effectively recover from infection. Recurrence (not reinfection) can occur in some animals. CNS involvement or severe pulmonary infection carries a higher mortality rate. If there is ocular involvement, vision may be lost and, in fact, the eye may remain infected. For this reason, enucleation of non-visual eyes is recommended.

Histoplasmosis

Histoplasmosis refers to the systemic disease caused by Histoplasma capsulatum. Histoplasmosis is found throughout the world. Histoplasma capsulatum has been identified in the soil of 31 states in the United States. Clinical disease is most common in the river valleys (as described above). This is a dimorphic fungus that exists in the environment in a saprophytic mycelial form. Warm, humid environments with nitrogen-rich soil are most conducive to fungal growth. The mycelial form reproduces sexually resulting in infective spores.

Disease occurs in dogs and cats. Cats tend to be younger and female. Dogs also tend to be younger and sporting breeds may be at increased risk. The disease does have a seasonal occurrence in some, but not all, regions. Infective spores are inhaled, transformed into yeasts and then disseminated via vascular or lymphatic routes. Because some animals only have involvement of the GI tract it has been suggested that the GI tract may also be a site of initial infection. More common sites of infection include the lungs, GI tract, lymph nodes, liver, and spleen. Less common is involvement of the eyes, skin, bones, and CNS. Common clinical findings include fever, anorexia, weight loss, pale mucous membranes, dyspnea, cough (dog > cat), lymphadenopathy (cat > dog), and hepatosplenomegaly.

Bloodwork may reveal a mild anemia due to chronic disease/inflammation and intestinal bleeding. A moderate luekocytosis consistent with chronic inflammation may also be seen. Cytopenias (neutropenia, anemia, thrombocytopenia) may also be seen due to bone marrow infiltration. Rarely, H. capsulatum yeasts can be found in peripheral white blood cells. Hyperglobulinemia and hypercalcemia can be seen for reasons discussed above. Hypoalbuminemia can be seen with liver dysfunction or intestinal involvement as well. Liver enzymes and bilirubin may be increased with hepatic involvement.

Radiographic findings within the thorax include diffuse interstitial changes that sometimes appear nodular or mass-like. Tracheobronchial lymph nodes are frequently enlarged in dogs. Mineralization of the pulmonary parenchyma and tracheobronchial lymph nodes may be seen in dogs. Abdominal radiographs are unremarkable even with intestinal involvement. On abdominal ultrasound hyperechoic nodules in the liver, thickened intestinal walls and mesenteric lymphadenopathy may be noted. Radiographic changes, less common than with blastomycosis, include osteolysis, periosteal proliferation and soft tissue swelling.

Diagnosis is made as described for blastomycosis by identification of the organism via cytology or histopathology. Typically multiple yeasts are found in cells of the mononuclear phagocyte system (lymph nodes, spleen, liver). In the cat, cytology of the bone marrow, lymph nodes and airways are most likely to yield organisms. In the dog a rectal scrape, airway cytology and aspirates of the liver, lymph nodes, spleen, and bone marrow are most likely to yield organisms. Histopathology of affected areas reveals organisms as well as granulomatous or pyogranulomatous inflammation. Antibodies are unreliable indicators of infection. As mentioned for blastomycosis, there is an antigen test developed for the detection of a capsular antigen that cross reacts between several different fungal organisms. Again, this test may document infection but can not determine the organism involved. PCR can be utilized for the diagnosis of histoplasmosis as well. Culture can be performed but is not typically necessary or recommended.

Itraconazole is currently the antifungal treatment of choice. Fluconazole does not appear to be as effective. Amphotericin B is recommended for CNS involvement or severe infection. As discussed above, posaconazole and voriconazole may also be used but experience with these drugs is limited. Glucocorticoids have been used for reasons described under blastomycosis.

The prognosis for dogs and cats with respiratory infections or mild clinical disease is good. For animals with CNS, ocular or severe clinical disease the prognosis is more guarded.

Coccidiomycosis

Coccidioides refers to the systemic disease cause by Coccidioides immitis and Coccidioides posadasii. This is a dimorphic fungus that exists in the mycelial phase in the soil indefinitely. This fungus is only found in arid low elevations such as the southwestern US (San Joaquin Valley, southern Arizona, southern New Mexico, Southern Texas), Mexico, Central America, and South America where there is sandy, alkaline soil with high environmental temperatures. Rain and wind are often associated with epidemics. The arthroconidia from the mycelial phase are infective.

Disease occurs in man, dogs and cats primarily via inhalation of infective arthroconidia. Cutaneous inoculation can occur but is uncommon. After entering the airways, cell-mediated immunity may limit infection or organisms may spread via lymphatics or hematogenous routes. Involvement of the respiratory tract, bones, eyes (chorioretinitis, uveitis), heart/pericardium, testicles, brain, and spinal cord are most common in dogs. In cats, skin and ocular involvement are most common. Signs typically develop several months after initial infection. Common clinical findings include fever, anorexia, weight loss, weakness, cough, lameness, lymphadenopathy, draining tracts, seizures, uveitis, and blindness. Signs consistent with congestive heart failure may be seen with myocardial and pericardial involvement.

Bloodwork may reveal a non-regenerative anemia, leukocytosis, hypoalbuminemia, and hyperglobulinemia for reasons discussed previously. Hypercalcemia is not reported with coccidiomycosis in dogs and cats.

Radiography is the imaging modality used most commonly. Thoracic radiographs most commonly reveal an interstitial pattern and tracheobronchial lymphadenopathy. Occasionally a nodular or alveolar pattern is seen. Pleural and pericardial effusion (echocardiography) may be seen. Radiographs of affected bones show osteolytic and proliferative lesions.

As with other fungal organisms, definitive diagnosis is made by organism identification through cytology, histopathology and culture. Because of the location of the infection, cytologic and histopathologic diagnosis can be difficult. Lymph nodes, draining tracts, airway samples (lower yield), vitreal samples, and csf can be evaluated for organisms. Histopathology will reveal pyogranulomatous inflammation and organisms. Serology is often used to identify diseased animals in the absence of organism detection. There are several different antibody tests that measure IgG and IgM. The preferred test is AGID which measures both using immunodiffusion tube precipitation (IgM) and immunodiffusion complement fixation (IgG). Measuring IgM is more likely to pick up earlier infections and IgG more chronic infections. IgG titers > 1:8 are considered positive. It is important to remember that many exposed, but not clinically affected animals will have positive titers for IgG (usually < 1:4) and some animals with active infection will have negative titers. Titers can also be used during therapy but should not be used as the sole criteria because the titers in some dogs fail to decrease dramatically with treatment. They may be helpful, however, in determining if therapy is ineffective (rising titers). Culture is not routinely performed because of the human health hazard.

Treatment is typically with the azoles. All azoles appear to be effective. Ketoconazole is most likely to be associated with side effects. Fluconazole may be preferred with CNS or ocular involvement. Treatment is for months to years.

Boney infection can be difficult to impossible to clear. Animals with CNS involvement carry a poor prognosis. Cats improve with treatment but commonly relapse and may require lifelong treatment.

Cryptococcosis

Cryptococcosis refers to the systemic disease caused, most commonly, by Cryptococcus neoformans and, less commonly, Cryptococcus gattii. Cryptococcosis occurs worldwide. Cryptococcus neoformans is found worldwide but C. gattii is limited to tropical and subtropical regions. Cryptococcus neoformans has been found in high concentrations in bird (particularly pigeon) excrement and C. gattii has been found in high concentrations in living and decaying trees. This is a dimorphic fungus that is typically found in the yeast form in both the environment and tissues. The yeast form in the environment is infective and can remain infective for up to two years in the environment.

Disease occurs in man and many different mammals. Disease is much more common in cats than dogs. Transmission is believed to be via inhalation of basidiospores or dessicated yeasts. Colonization of the nasal passages is most common in dogs and cats with signs related to upper respiratory disease (sneezing, stertor, nasal discharge) as well as swelling of the bridge of the nose, nasal plate or face. Basidiospores and yeast may be trapped in the alveoli and result in primary colonization of the lower airways but this is much less common. Cutaneous inoculation is possible but unlikely. Spread may be via direct extension from the nasal passages or hematogenous. This may result in the ocular abnormalities and CNS signs. Granulomatous chorioretinitis, retinal detachment and optic neuritis can occur. Central nervous signs include depression, ataxia, seizures, circling, blindness, head pressing, cranial nerve deficits, paresis, and cervical pain. Dogs tend to be younger and the American Cocker Spaniel, Labrador Retriever, Great Dane, Doberman pinscher, German shepherd dog, and other sporting breeds may be more commonly affected. Cats tend to be younger and female with Siamese, Birmans and ragdolls more commonly affected. Immunosuppression may predispose to disease. More common sites of infection include the nasal passages, nasopharynx, lower respiratory tract, central nervous system, eyes, and skin. Less common is involvement of lymph nodes, bone, salivary glands, and intestinal tract. Common clinical findings include weight loss, lethargy, sneezing, nasal discharge, swelling of the nose or face, stertor, and difficulty breathing. With neurologic involvement depression, behavior changes, seizures, vestibular signs, paresis, paralysis, and blindness may occur. Blindness, optic neuritis, granulomatous chorioretinitis, and retinal detachment are more common ocular findings. Papules, nodules and ulcers may be found with involvement of the skin.

Radiographs of the nasal passages may reveal boney destruction, soft tissue swelling and soft tissue density within the nasal passages. Thoracic radiographs are often normal but occasionally nodules may be noted. Cross-sectional imaging can be performed of the central nervous system. Lesions are identifiable in the optic chiasm, brain and spinal cord. Computed tomography of the head will reveal boney destruction, soft tissue swelling, and a soft tissue mass with contrast enhancement in the nasal passages. Lesions within the brain and spinal cord may be focal or multifocal and contrast enhancing. Magnetic resonance imaging of the brain and spinal cord may reveal solitary or multifocal parenchymal lesions in various locations that contrast enhance. Meningeal enhancement is common on MRI as well.

Diagnosis is most commonly made by organism identification from cytologic or histologic samples of affected tissue. Nasal wash/swabs, tissue aspirates (lymph nodes, lung, skin, vitreous), airway samples, urine, and csf may yield organisms for cytologic diagnosis. Histopathology incorporating fungal stains as well as immunohistochemistry can be used. The latex agglutination test for detection of a polysaccharide capsular antigen is used to detect antigen in the serum and csf. This test is often used when disease is suspected but organisms are not readily identified as well as in animals in which intracranial disease is suspected because of possible morbidity associated with csf collection. Titers of 1:2 or greater are considered positive. Polymerase chain reaction has also been used for identification. Culture may also be performed but is not commonly done. Unlike the other systemic fungi discussed, culture does not pose a health hazard to man.

Infected tissues can be surgically excised to improve response to treatment. Amphotericin B (with flucytosine in cats) is recommended for severe or CNS infections in cats and dogs. Fluconazole is commonly used because of good penetration into the CNS and eyes. For infections that do not involve the eye or CNS, itraconazole may be used although it has been effective in animals with CNS infections.

Animals have to be treated for many months (even over a year) and those with CNS disease carry a more guarded prognosis. Serology for capsular antigen has been used to monitor therapy.

References

Davidson AP. Coccidioidomycosis in Textbook of Veterinary Internal Medicine 7th ed SJ Ettinger, EC Feldman (eds) pp 996-1001.

Greene CE. Histoplasmosis in Infectious Diseases of the Dog and Cat 3rd ed. Greene CE (ed) Elsevier pp. 577-84.

Greene RT. Coccidiomycosis and Paracoccidiomycosis in Infectious Diseases of the Dog and Cat 3rd ed. Greene CE (ed) Elsevier pp. 598-608.

Legendre AM. Blastomycosis in Infectious Diseases of the Dog and Cat 3rd ed. Greene CE (ed) Elsevier pp. 569 – 576.

Malik R, Krockenberger M, O'Brien CR, et al. Cryptococcosis in Infectious Diseases of the Dog and Cat 3rd ed. Greene CE (ed) Elsevier pp. 584-98.

Sykes JE, Sturges BK, et al. Clinical signs, imaging features, neuropathology, and outcome in cats and dogs with central nervous system cryptococcosis from California. J Vet Int Med 2010;24(6):1427-38.

Taboada J, Grooters AM. Histoplasmosis, Blastomycosis, Sporotrichosis, Candidiasis, Pythiosis in Textbook of Veterinary Internal Medicine 7th ed SJ Ettinger, EC Feldman (eds) pp 971 – 987.

Taboada J, Grooters AM. Cryptococcosis in Textbook of Veterinary Internal Medicine 7th ed SJ Ettinger, EC Feldman (eds) pp 988 – 92.