Robert Sherding United States
This will discuss the pulmonary manifestations and treatment of the four major systemic mycoses of dogs and cats: histoplasmosis, blastomycosis, coccidioidomycosis, and cryptococcosis.
The cause of histoplasmosis, Histoplasma capsulatum, is a dimorphic soil borne fungus found in many temperate and subtropical regions of the world. In North America, the disease is most prevalent in the river valley regions of the central United States, especially in areas bordering the Mississippi River and its tributaries. At ambient temperature, soil enriched by decomposing nitrogenous matter (e.g., feces of birds or bats) provides an ideal growth media for the mycelial phase of Histoplasma. The principal route of infection is by inhalation of airborne spores and mycelial fragments in windblown soil. Histoplasma organisms transform into a yeast phase that causes intracellular infection of pulmonary macrophages. Widespread hemolymphatic dissemination to virtually any tissue or organ system can occur. The outcome of exposure is influenced by level of exposure; age (clinical disease is most common in young animals less than four years of age); breed (highest prevalence in sporting and hound breeds, perhaps due to higher exposure risk); immunosuppressive factors (corticosteroids may enhance dissemination); and host cell-mediated immunity. Inapparent infections without evidence of clinical disease are common.
Inapparent, self-limiting infection confined to the respiratory tract is the most common outcome of natural infection. It is recognized radiographically as multiple discreet calcified interstitial foci (inactive encapsulated or healed lesions) and sometimes calcified tracheobronchial lymph nodes. The acute pulmonary form of histoplasmosis is characterized by severe fulminant granulomatous pneumonia with signs of cough, dyspnea, fever, and severe malaise. The radiographic findings are pronounced diffuse linear or nodular interstitial pulmonary infiltrates, often with patchy coalescing densities and moderately enlarged tracheobronchial lymph nodes. The chronic pulmonary form is more common than the acute form and is characterized by chronic granulomatous pneumonia (diffuse or multifocal with marked tracheobronchial lymphadenopathy that causes extrinsic airway compression. The signs include chronic cough and mild dyspnea with variable weight loss and fever. Radiographically, massive enlargement of the tracheobronchial lymph nodes and variable linear or nodular interstitial infiltrates are seen.
Intestinal histoplasmosis is the most common extrapulmonary form in dogs and may represent dissemination or primary infection by ingestion. The colon, small intestine, or a combination of both can be affected by extensive granulomatous thickening of the bowel wall and mucosal ulceration, often accompanied by mesenteric and visceral lymphadenopathy. Intractable diarrhea and progressive weight loss are the most consistent clinical signs. Other extrapulmonary sites of infection include liver (hepatomegaly, icterus, ascites); spleen (splenomegaly); lymph nodes (peripheral or abdominal lymphadenopathy); bone marrow (anemia); peritoneum (omental masses, mesenteric adhesions, nodular or granular serosal surfaces); eyes (exudative anterior uveitis, multifocal granulomatous chorioretinitis, optic neuritis); central nervous system (ataxia, seizures, etc.); skin (fistulous tracts that drain pus or skin and subcutaneous nodules that may be ulcerated); bone (lameness associated with proliferative or lytic boney lesions); and oral cavity (ulcers). Most cats with histoplasmosis develop disseminated involvement.
Histoplasmosis should be suspected based on clinical signs in animals from endemic areas. The results of routine laboratory evaluations are variable and nonspecific. Radiographic findings in the pulmonary form are often highly suggestive of histoplasmosis. Serology provides a presumptive diagnosis, but identification of the Histoplasma organisms is necessary for definitive diagnosis. Hematology may reveal normocytic-normochromic nonregenerative anemia, neutrophilic leukocytosis or neutropenia with left shift, monocytosis, and mild thrombocytopenia and macroplatelets. Cats can develop pancytopenia.
Thoracic radiography may reveal linear or nodular (“miliary”) interstitial pulmonary infiltrates, hilar density around the tracheal bifurcation due to tracheobronchial lymphadenopathy, coalescing patchy alveolar infiltrates, calcified pulmonary interstitial nodules (healed lesions), and calcified tracheobronchial lymph nodes.
Serologic tests that detect anti-Histoplasma antibodies are not sufficiently reliable for definitive diagnosis; thus, every effort should be made to confirm infections through identification of the Histoplasma organisms. A complement fixation titer of 1:16 or greater or a positive agar-gel immunodiffusion (precipitin) test are considered suggestive of histoplasmosis. Unfortunately, these tests often yield false-negative results in animals with histoplasmosis. Prior exposure may cause a false-positive result. In addition, other mycotic infections (e.g., blastomycosis) may crossreact on serodiagnostic tests for histoplasmosis and anticomplementary sera may make complement fixation unusable in some animals.
Definitive diagnosis of histoplasmosis requires identification of Histoplasma organisms in cytology, biopsy, or culture specimens. Cytologic specimens obtained by airway washings, bronchoscopic alveolar lavage, or fine-needle lung aspiration are generally the most practical and high-yield methods for definitive diagnosis of histoplasmosis. Wright, Giemsa, or Diff-Quick stains are ideal for identification of Histoplasma in cytology preparations. The organisms are found most often intracellularly within the cytoplasm of macrophages as round to oval bodies, 2 to 4 um in size, surrounded by a characteristic clear halo or “pseudocapsule” that results from shrinkage during staining. Respiratory specimens can also be used to culture the fungi in Sabouraud's media; however, these fungi are difficult to isolate and mycelial culture growth can be infectious for humans.
Biopsies of affected tissues reveal granulomatous inflammation, but organisms are usually sparse and difficult to see with H & E stain. Detection of organisms in biopsies may be facilitated by use of special fungal stains such as PAS, Grocott-Gomori methenamine silver, or Gridley.
Oral itraconazole is the treatment of choice for histoplasmosis. Treat for at least two months beyond clinical resolution, which usually requires a total of four to six months of therapy. For refractory cases of ocular and neurologic involvement, use fluconazole for its better penetration of the eyes and CNS. Consider combining amphoteracin B and itraconazole for initial treatment of severe fulminant pulmonary or progressive disseminating disease. Lipid-complexed amphoteracin formulations allow higher dosages with less toxicity, but the cost is higher. Ketoconazole is less effective and has more side effects than other azoles; however, it can be used to treat histoplasmosis when cost is a limiting factor.
Blastomyces dermatitidis is a dimorphic soilborne fungus with a geographic distribution similar to Histoplasma. The organisms reside in sandy, acidic soil near water. Most infected dogs live within 400 meters of water. Inhalation of soilborne spores is the primary route of infection and leads to mycotic pneumonia. Focal skin infection can occur from direct cutaneous inoculation through a wound. Extrapulmonary dissemination is very common in blastomycosis. Dogs are considered highly susceptible to blastomycosis and the canine infection rate in endemic areas is 10 times the human infection rate. Blastomycosis is rare in cats.
Young male large-breed dogs are infected most frequently, probably because of increased exposure through outdoor activities. Nonspecific signs of fever, anorexia, weight loss, and depression are common. Signs may be acute (days) or chronic (weeks to months). Lung lesions are present in 85% of cases. Cough and dyspnea are typical presenting signs of the pulmonary form. Respiratory manifestations can include (in decreasing order of frequency): acute or chronic interstitial pyogranulomatous pneumonia, usually involving all lung lobes diffusely, sometimes focally; tracheobronchial lymphadenopathy; and pleural effusion. Blastomycosis very commonly disseminates, especially to the skin (40% of cases), eyes (40% of cases), and peripheral lymph nodes (60%), but to lesser extent also to the bones (distal limb lameness and swelling), CNS (seizures, dementia, blindness, ataxia), male genitalia, oral cavity, and nasal cavity.
Hematology typically reveals a regenerative neutrophilic leukocytosis, lymphopenia, monocytosis, and mild nonregenerative anemia. Thoracic radiography usually reveals a nodular (usually miliary) or diffuse pulmonary interstitial infiltrate and occasionally a moderate tracheobronchial lymphadenopathy. Less frequent findings include alveolar infiltrates, lobar consolidation, focal solitary nodules, pleural effusion, and cavitary lesions. Serology provides a presumptive diagnosis of blastomycosis based on a positive agar gel immunodiffusion test (AGID 90% reliable) or a complement fixation titer of 1:32 or greater (less reliable than the AGID). Cytology or biopsy identification of Blastomyces organisms provides a definitive diagnosis. The best choice for specimens and method of procurement depends on sites of involvement (such as transtracheal washing, bronchoalveolar lavage, fine-needle lung aspirate, skin impression smears, lymph node aspirates, fluid specimens). Blastomyces in tissues appears as extracellular yeast (5–20 um) with broad-based budding and a prominent double refractile cell wall. Any routine cytology stain can be used. The inflammatory pattern is pyogranulomatous. The use of in-clinic culturing is not recommended because mycelial growth poses a risk of human infection.
Oral itraconazole is the treatment of choice for blastomycosis. Fluconazole is also effective. Ketoconazole is less effective and has more side effects; however, it can be used when the cost of itraconazole is a limiting factor. Treat for at least two months beyond clinical resolution, which usually requires a total of four to six months of therapy. Amphoteracin B is also effective, but has the disadvantages of parenteral administration and frequent nephrotoxicity. Consider Amphoteracin B in rapidly progressive disease for its rapid onset of action in combination with itraconazole. Lipid-complexed amphoteracin formulations allow higher dosages with less toxicity, but the cost is higher.
Coccidioides immitis is a soilborne fungus distributed geographically to the dry desert-like regions of the Southwestern United States. In the soil, Coccidioides grow as mycelia that form arthrospores. Infection occurs by inhalation of these soil-borne and wind-blown arthrospores. Cutaneous inoculation may occur, but rarely. In body tissues, Coccidioides form large spherules (20-100 um) that release hundreds of endospores.
Subclinical pulmonary infection is the most common form. Clinically apparent pulmonary disease is characterized by acute or chronic granulomatous pneumonia and tracheobronchial lymphadenopathy with signs of cough, fever, malaise, and occasionally dyspnea. Extrapulmonary dissemination is usually chronic and may involve the bones and joints (mostly osteoproliferative bone reaction causing lameness and painful swelling); abdominal viscera (spleen, liver, lymph nodes, omentum, kidneys); heart and pericardium (myocarditis, pericarditis, congestive heart failure); eyes (uveitis); CNS; male genitalia; and skin (usually ulcerated nodules and fistulas over bone lesions). Bone involvement is most common in dogs whereas skin lesions are the predominant finding in cats.
Hematology may show a variable leukocytosis, monocytosis, and nonregenerative anemia. Radiography reveals granulomatous pneumonia and hilar lymphadenopathy similar to that described for histoplasmosis. With cardiac involvement, pericardial effusion or pulmonary edema may be seen. Dissemination to bone is common, especially to the distal aspects of the long bones, and it results in multifocal osteoproliferative lesions on radiographs.
A reasonably reliable presumptive diagnosis can be made on the basis of serologic tests such as the tube precipitin, complement fixation, AGID, and ELISA tests which detect the early IgM antibody response and the later and sustained IgG response. The IgM response becomes positive two weeks post-exposure and persists for four to six weeks. IgM also may be detected at the time of dissemination or recrudescence in association with high IgG levels. High IgG titers (> 1:64) generally indicate severe pulmonary or disseminated disease.
Definitive diagnosis again depends on identifying the organisms (spherules) in affected tissues using cytology or biopsy; however, spherules may be difficult to find in some cases. Lesions are pyogranulomatous. Culturing is too hazardous to recommend because mycelial growth is highly infectious for humans.
Coccidioidomycosis is usually treated with one of the oral azole drugs (ketoconazole, itraconazole, or fluconazole) for a minimum of eight to 12 months, and sometimes much longer or indefinitely. Amphoteracin B is not quite as effective but can be used in animals that do not tolerate oral azole drugs. Preliminary evidence indicates that lufenuron, a chitin synthesis inhibitor licensed for control of fleas in dog and cats, may be an effective treatment when given daily (rather than monthly as for fleas). Regardless of treatment, relapses are common even after many months of apparent remission, especially when bone is involved.
Cryptococcus neoformans is found in many geographic regions and infection is acquired from inhalation of soil-borne organisms or in urban areas from inhalation of organisms found in pigeon excreta. The organisms are budding yeasts (4–7 um) that possess a prominent polysaccharide capsule. This thick capsule is essential to the pathogenicity of this fungus in that it inhibits plasma cell function, phagocytosis, leukocyte migration, and complement. The capsule also allows the organisms to standout in stained cytology preparations for easy identification and is the basis for the cryptococcal capsular antigen diagnostic test.
In cats, Cryptococcus has a predilection for the nasal cavity where the airborne organisms initially deposit, accounting for the chronic granulomatous rhinitis and sinusitis seen in at least 50% of the cats with the disease. In contrast to cats, clinically evident nasal disease is rare in dogs with cryptococcosis; instead, CNS and eye involvement are the predominant findings. Surprisingly, lung involvement is only rarely evident clinically, yet 50% of dogs and cats have lung lesions at necropsy. Fever occurs in less than 25% of the cases; in fact, temperatures exceeding 37 C inhibit Cryptococcus.
The principal signs of nasal involvement are unilateral or bilateral mucopurulent or bloody nasal discharge, sneezing, sniffling, deformity of overlying nasal bones, and mucinous-appearing nasal granulomas at the nostril. The preferred sites for dissemination are the CNS, eyes, and skin. CNS involvement from hematogenous spread or local extension through the cribiform plate results in diffuse or mass-like granulomatous meningoencephalitis or myelitis. The signs may include seizures, circling, head pressing, blindness, dementia, ataxia, paresis, or cranial nerve (CN) deficits. Ocular involvement: may include granulomatous (exudative) chorioretinitis, anterior uveitis, or optic neuritis. Skin involvement: usually manifests as firm nodules that rapidly enlarge and then ulcerate and ooze, mostly in the head area, often near the nostrils. Other dissemination sites: may include peripheral lymph nodes (especially submandibular), pharynx and oral cavity, kidneys (30% have granulomas at necropsy), liver, spleen, heart, and skeletal muscle.
Hematology is often normal, except for occasional neutrophilia or eosinophilia. Nasal radiographs: may indicate nasal bone lysis or expansion, or an abnormal soft tissue density within the nasal cavity or frontal sinus. Serology provides a presumptive diagnosis based on detection of capsular antigen in serum, CSF, or urine using latex agglutination or ELISA. Commercial capsular antigen test kits have high sensitivity and specificity; however, false negatives occur, especially in nondisseminated disease. False positives can occur in patients treated with hetastarch and in CSF contaminated with talc from latex gloves.
Definitive diagnosis requires identification of the organisms in cytologies (e.g., nasal exudate, cerebrospinal fluid, skin exudate or impressions, lymph node aspirates, urine, oculo-centesis) using Gram, PAS, new methylene blue, or India ink stains or in biopsies using mucicarmine, H & E, PAS, or silver stains. Cryptococcus can also be cultured from similar specimens on Sabouraud's media.
Treat cryptococcosis with oral itraconazole or fluconazole for at least two months beyond clinical resolution, which usually ranges from six to 10 months (mean, 8.5 mo.). When the eyes or CNS are involved, fluconazole is preferred because of its better penetration into these tissues. Ketoconazole is not as effective and has more side effects than other azoles; however, it can be used when cost is a limiting factor. Flucytosine combined with amphoteracin B is also an effective treatment, but has the disadvantage of greater adverse side effects, especially nephrotoxicity.
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