Coccidioidiomycosis is a disease caused by two distinct species of Coccidioides that can accurately be distinguished by genetic analysis. This dimorphic soilborne fungus is restricted to certain geographic regions. It grow in soil and culture medium as an ascomycetous fungus, whereas in tissues it form spherules. The disease has been reported in a wide variety of mammalian hosts and a few captive reptiles, but not in avian species.94 The history of the disease is reviewed in Web Box 60-1 and by other authors.55 Unlike other fungal pathogens, Coccidioides spp. are haploid organisms with no known observed sexual state.25 Isolation from the environment has been difficult, even at known sites of exposure. Molecular techniques have helped identify where these organisms exist in nature.48 The vegetative mycelia germinate to form thick-walled, barrel-shaped, rectangular, multinucleate arthroconidia, 2 to 4 µm wide and 3 to 10 µm long (Fig. 60-1). Within the mycelium, viable arthroconidia alternate with smaller, thin-walled, nonviable cells and can persist within the soil indefinitely. Activities that disturb the soil cause the intervening nonviable cells to degenerate, releasing the environmentally resistant arthroconidia, which are dispersed by wind. The arthroconidia can germinate to yield new hyphae or serve as the infecting form for animals and people (Fig. 60-2). When inhaled by a host, arthroconidia, at higher temperature (37° C [98.6° F]) and in the presence of increased carbon dioxide, convert into a different morphologic form. They shed all but one nucleus, round up, and enlarge to produce an immature spherule. The nucleus undergoes division, which is followed by inward partitioning of the cytoplasm, resulting in a mature spherule with endospores in the center. The spherule gradually enlarges to 20 to 200 µm in diameter, and eventually breaks open to release 200 to 300 endospores (3 to 5 µm). Each endospore has the potential to form a new spherule if incubated at 37° C, or mycelia at room temperature. Transformation from arthroconidia to immature spherules can be completed within 2 to 3 days. In the host, intact spherules are poorly chemotactic for neutrophils. Neutrophils that do attach cannot penetrate the wall of the spherule (Fig. 60-3). However, the endospores are the most vulnerable stage of Coccidioides spp. in the body. They attract a large number of neutrophils and are small enough to be phagocytized. In nature, the mycelial phase of Coccidioides spp are only found in a specific ecologic region, the Lower Sonoran life zone. Geographically, the Lower Sonoran life zone is within the southwestern United States, Mexico, and Central and South America (Guatemala, Honduras, Colombia, Venezuela, Paraguay, Brazil, and Argentina) (Fig. 60-4).52 This zone is characterized by sandy, alkaline soils; high environmental temperatures (summer mean above 26.6° C [79.9° F]; winter mean 4° C to 12° C [39.2° F to 53.6° F]); low annual rainfall (3 to 20 inches); and low elevation (sea level to a few hundred feet). During prolonged periods of high temperature and low soil moisture, Coccidioides spp. survive below the soil surface at depths as great as 20 cm, where competitive organisms are few. After a period of rainfall, Coccidioides spp. replicate in the upper soil surface, sporulates, and release a large number of arthroconidia to be disseminated by the wind. Epidemics in people have occurred after dust storms, following the rainy season, or after earthquakes.91 People and animals residing in or visiting endemic areas are at high risk of exposure during these periods.12 Endemically, the incidence of disease is highest in the early fall and winter, when the soil is dry and crops are being harvested. Occupational and recreational exposure of people and animals in the outdoors leads to a greater risk of infection. In the United States, the disease is often referred to as valley fever, after the occurrence of an epidemic in the San Joaquin Valley of California, but it is also prevalent in Arizona and southwestern Texas. The disease is less common in New Mexico, Nevada, and Utah. A few endemic areas are found in Central and South America, particularly Venezuela. From a taxonomic perspective, Coccidioides immitis is the species of organism distributed in the San Joaquin Valley, whereas Coccidioides posadasii, formerly termed the non-California isolate, is found in all other endemic areas.34 Although the majority of infections in animals and people are diagnosed within the southwestern United States, an occasional case may be identified outside this area. Usually, individuals involved in these “stray” cases have a history of residence or travel within an endemic area. The patient may have been in an endemic area several years earlier, and the organism had remained dormant for some time.18 Serologic surveys indicate that most human and canine inhabitants in endemic areas become infected; however, most infections are subclinical or cause only mild, transient respiratory signs. Estimates are that only 40% of infected people develop respiratory symptoms, and very few develop systemic manifestations. In the remaining 60%, the only evidence of infection is seroconversion. In contrast to other species, dogs appear more susceptible to developing disseminated disease. In Arizona, a serosurvey of dogs in Pima and Maricopa counties revealed that 28 of 104 (28%) young dogs developed antibodies to Coccidioides spp. after 1 year, and in some instances 2 years, of monitoring. A cross-sectional analysis revealed that 32 of 381 (8%) dogs tested in this endemic area had positive antibody tests.93 The disease is highly infectious, but not typically contagious. The major route of infection is by inhalation. Very few (fewer than 10) arthroconidia must be inhaled to produce disease. The incubation period from inhalation to onset of abnormal respiratory signs is 1 to 3 weeks. Primary localized infection of skin lesions from penetrating wounds has rarely been reported. Experimentally, intradermal inoculation or skin scarification produces only localized infection in a small percentage of animals. After inhalation, the arthroconidia first enter the bronchioles and alveoli and then extend into the peribronchiolar tissue, eventually causing subpleural lesions. The first cellular response is in neutrophils, followed by monocytes, lymphocytes, and plasma cells. As with all fungal infections, cell-mediated immunity is more important than humoral immunity in eliminating infection. Mononuclear phagocytes are responsible for removing the organism from tissues and body fluids. There is good evidence that mannose receptors play a role in this phagocytosis.87 Endospores are most susceptible to host cell–mediated immunity. The wall of the spherules provides a means of immune evasion by the organism. Although not protective, antibody response to two different antigens of the fungus has been used to detect infection (see Diagnosis). Recovery from initial infection in people results in lifelong immunity, but resistance to reinfection in animals is uncertain. With massive exposure, pregnancy, or depressed cellular immunity, pulmonary infection can become more extensive, and the organism can invade the hilar lymph nodes and distant tissues. Interleukin levels may play a role in resistance to infection, as has been demonstrated in mice.33 In people, race is a known risk factor,80 but no definite breed predilection has been defined in dogs. In one report,89 the authors stated that greyhounds may be more susceptible.89 If disease progresses beyond the hilar lymph nodes, which it can do within 10 days of exposure, it is considered to have disseminated. Dissemination involves the reproductive cycle from spherules to endospores to new spherules. If the disease disseminates, the organs that are usually affected are, in order of decreasing frequency, bones, eyes, heart and pericardium, testicles, brain, spinal cord, and visceral organs (primarily spleen, liver, and kidney). Ocular lesions begin as a chorioretinitis and extend into the anterior chamber causing panophthalmitis. The intestinal mucosa and endocardium are rarely affected. Virtually all other tissues can be affected. Signs referable to dissemination usually occur approximately 4 months after pulmonary signs develop, but this period is variable, and the respiratory infection may have never been noticed. Disseminated cases usually follow a chronic course of months to years. However, the author has seen disseminated disease in a puppy only 10 weeks of age. Widespread dissemination was also observed in a dog with concurrent multicentric lymphoma.57 Intrauterine transmission has typically been thought not to occur, because of the large size of the spherules. Neonatal disease transmission has generally been thought to occur from contact of the neonate with the female genital tract or vaginal secretions as the neonate is being born. However, in a case report of a human infant delivered by cesarean section, transplacental transmission from mother to baby was well documented.19 This baby girl developed disease at 15 days of age. Although very rare, reports exist of Coccidioides spp. fungal hyphae, rather than endospores or spherules, being recovered from disseminated infections involving the central nervous system (CNS) in people.69,103 In many instances, but not always, this type of infection has been found in association with a surgically placed CNS shunt for hydrocephalus.51 This unusual form of mycelial infection has not been reported in animals. Signs of right- or left-sided congestive heart failure can also occur. Cardiac dysfunction arises from disturbances in blood flow, conduction, and myocardial contractility, resulting from granulomatous lesions in the pericardium.97 The lesion often spreads within the pericardial sac, resulting in constrictive pericarditis. Cranial or paraspinal hyperesthesia is typical for dogs with early CNS localization, as a result of meningeal localization and inflammation.59 Seizures, ataxia, behavioral changes, and coma have been associated with subsequent encroachment on the CNS by granulomatous meningoencephalomyelitis.13,92a Lameness is usually accompanied by painful bone swellings (Fig. 60-5). Bone lesions usually are initially localized to one bone, but may progress to involve multiple sites. The lesions generally occur in the long bones, in the distal diaphysis, metaphysis, and epiphysis, and a combination of bony lysis and production is usually noted. Lesions occur in the axial skeleton, but only at a 10% prevalence compared with the appendicular skeleton. Joint infection is not typical, although secondary immune-mediated polyarthritis can develop in infected dogs. Most cutaneous involvement results from systemic hematogenous spread of the organism. Skin lesions that begin as small bumps and progress to abscesses, ulcers, or draining tracts are almost always found over sites of infected bone (see Fig. 60-5). Naturally occurring primary cutaneous infection from penetrating injury is extremely rare in dogs.82 Signs associated with Coccidioides spp. infection in cats are similar to those described in dogs.50 However, skin lesions are the most frequent type of infection found in cats. Skin infections without underlying bone involvement are common. Fever, inappetence, and weight loss are commonly found concurrently with skin lesions. Coughing, wheezing, and respiratory difficulties are only occasionally recognized with feline Coccidioides spp. infections, possibly because cats limit their physical activity. Appendicular bone lesions, similar to lung lesions, are rarely recognized in feline infections, in contrast to canine infections. When bone lesions are present in cats, the radiographic changes are similar to those observed in dogs. Ocular lesions of chorioretinitis and anterior uveitis occur with about the same frequency in cats as they do in dogs. In addition to intraocular lesions, cats can also develop subpalpebral or periorbital periocular swellings (see Systemic Mycoses of Dogs and Cats, Chapter 92).101a One report describes a discrete, intraparenchymal, granulomatous lesion of the spinal cord in a cat.35 This caused progressive hindlimb paraparesis and weakness of the rear legs. This type of lesion has not been previously described in humans or dogs. On a magnetic resonance imaging (MRI) study, it was contrast-enhancing and appeared intradural, but extramedullary. Thoracic radiographic findings vary with the severity of the disease. A diffuse interstitial pattern is most common, but is often mixed with a localized alveolar pattern (Fig. 60-6). Miliary to nodular interstitial densities may be found. If solitary nodules are found, they are often found in the periphery. If computed tomographic scans are used for evaluation of these nodules, central necrosis or cavitation may be found in up to 30% of the lesions.62 A halo of homogeneous attenuation around the nodule is often found. Pulmonary abscess formation, fibrosis, and bronchiectasis (rarely with calcification) may be sequelae to severe pulmonary infection. Hilar lymphadenomegaly is quite common, affecting most dogs with chronic illness, but calcification of the hilar lymph nodes or sternal lymphadenomegaly is rare. Pericardial and pleural effusion may develop secondary to right-sided myocardial failure or, more frequently, to pericarditis.97 Radiographic findings of osteomyelitis are typically a mixture of both lysis and production (Fig. 60-7). Reports of MRI changes in animals are lacking, except for the one report described previously of a contrast-enhancing spinal lesion in a cat. In people with acute meningitis, if MRI is performed, focal or diffuse enhancement may be found, along with ventricular enlargement and deep infarcts.32 As with other nodular interstitial diseases, false-negative results are common with transtracheal or endobronchial washings. The chance of a positive yield increases if alveolar disease is present. In human patients with diffuse lung disease, Papanicolaou’s (Pap) stain was found to be superior in detecting organisms, compared with 10% potassium hydroxide or calcofluor white.90 Spherules are frequently found in aspirates of enlarged lymph nodes and/or in impression smears of draining lesions (Fig. 60-8). CSF abnormalities include pleocytosis, with a predominance of neutrophils and a lesser number of mononuclear cells, and are consistent with granulomatous inflammation. Organisms may not always be observed. The organism can be seen in unstained preparations under reduced light as a large (10 to 80 µm), round, double-walled structure containing endospores. Ten percent potassium hydroxide can clear an unstained specimen, although stained preparations are more helpful. The organism is readily recognized with standard Wright’s stain, but to specifically stain the fungal structures, the best stains are Pap and periodic acid–Schiff (PAS). With Pap stain, the capsular wall is refractile and purple-black, the cytoplasm yellow, and the endospores red-brown. Not all spherules contain recognizable endospores. Smaller spherules may have a crumpled, transparent wall. With PAS stain, the wall is deep red to purple and the endospores are bright red. A large number of neutrophils may surround the spherules, making visualization difficult. Although spherules are not typically confused with fungal elements of other organisms, Cokeromyces recurvatus was misidentified as Coccidioides spp. in the peritoneal effusion of a cat with a jejunal perforation.74 Mycelial forms of Coccidioides spp. do not typically occur in samples from patients. Rarely, in human patients with type 2 diabetes, mycelial forms can be seen in pulmonary coccidioidomycosis. Typically, these patients have had chronic and cavitary pulmonary lesions.73 Spherules and endospores are often concurrently found with the mycelial form. Coccidioides spp. grow on a wide range of common fungal culture media and blood agar. No attempts should be made to culture and identify this organism within veterinary practices. Instead, samples should be sent to laboratories familiar with biosafety precautions (see Web Appendix 5, Laboratory Testing for Infectious Diseases in Dogs and Cats). The mycelial phase grows best at 25° C to 30° C. It usually grows within 3 days, but may require more time if the number of organisms in the sample is low. The characteristic pattern of alternating live and dead arthroconidia associated with the appearance of the fungal colony allows for presumptive identification, but additional in vitro and in vivo methods can further definitively identify the organisms. One notable phenotypic difference is that C. posadasii has slower growth rates on high-salt media when compared to that of C. immitis. Veterinarians, technicians, and laboratory personnel must recognize that arthroconidia from mycelial growth are highly infectious. Although no commercial genomic test currently exists for coccidioidomycosis, there are several studies demonstrating the usefulness of polymerase chain reaction or antigen tests in establishing the diagnosis in patient specimens.9,11,11 Despite the availability of these assays, there have not been controlled studies to determine their accuracy as clinical diagnostic tests. Genetic sequencing of the whole genome of isolates of Coccidioides spp. has been helpful in documenting transmission of infection through organ transplantation.31a Tests to detect antigenemia (galactomannan) have been developed and used on an investigational basis in rodents and people.31,41 Antigen detection would be helpful in early cases before seroconversion, or in patients with immunodeficiencies in which seroreactivity does not develop. Interference by various components in serum has been a major problem with antigen tests. However, newer techniques are being developed, and will likely be used in the future. Web Appendix 5 should be consulted for a list of laboratories that perform these serologic tests for coccidioidomycosis. The author has been involved in a study evaluating a newer antigen test in blood and urine of dogs, but the results were not favorable. Admittedly, part of the problem in determining the accuracy of the antigen test is that there is no gold standard among the antibody tests, on which the diagnosis was being based. When the organism cannot be demonstrated by cytology or biopsy, detection of antibodies to the organism is commonly used as a presumptive test. The two classic antigens for serotesting are the tube precipitin (TP) and complement fixation (CF) antigens. The names for these differently prepared antigens were based on the types of tests that were initially used to detect antibodies. The antibody response to the TP antigen is primarily IgM, whereas the antibody response to the CF antigen is associated more with IgG. For interpretation of TP and CF antibody titers in naturally infected dogs, and the antibody class they measure, refer to Table 60-1. Most laboratories no longer perform the TP and CF tests. Instead, latex agglutination, agar gel immunodiffusion (AGID) or enzyme-linked immunosorbent assays (ELISA) for IgM or IgG are respectively used. The results of these tests are typically reported as IgM or IgG positive or negative. Refer to Web Appendix 5 for laboratories that perform these tests. TABLE 60-1 Interpretation of Serologic Testing for Coccidioidomycosis in Dogs and Cats 2. Early infection; if disease suspected, repeat test in 4 to 6 weeks to detect positive TP or CF test results 3. Rapidly fatal, fulminating infection in severely immunocompromised animal
Coccidioidomycosis and Paracoccidioidomycosis
Coccidioidomycosis
Etiology
Epidemiology
Pathogenesis
Clinical Findings
Dogs
Cats
Diagnosis
Clinical Laboratory Findings
Medical Imaging Findings
Cytologic Findings
Fungal Isolation
Organism Detection
Antibody Detection
Dogs
TP Antibody: Negative
TP Antibody: Positive (Predominantly IgM)
CF Antibody: Negative
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