An Overview of Coccidioidomycosis

Jana Ritter, DVM; Julie L. Webb, DVM; Bruce E. LeRoy, DVM, PhD, Dipl. ACVP; Kenneth S. Latimer, DVM, PhD, Dipl. ACVP

Class of 2007 (Ritter) and Department of Pathology (Webb, LeRoy, Latimer), College of Veterinary Medicine, University of Georgia, Athens, GA, 30602-7388

Introduction

Coccidioidomycosis is a fungal disease caused by Coccidioides immitis, and less frequently, by Coccidioides posadasii.¹It was first recognized as a human disease in Argentina in 1892, and was first reported as a disease of animals in 1918, with a case of bovine infection. Since then, it has been found in both wild and domestic animals, including deer, tigers, mice, rats, squirrels, gorillas, monkeys, dogs, cats, sheep, cattle, horses, and reptiles.^2,3

Life Cycle

C. immitis is a soil-borne dimorphic fungus that has 2 stages in its life cycle:  the saprophytic and parasitic stages. The saprophytic mycelial phase contains the infectious arthroconidia and is found in the upper layer of the soil in endemic regions. With disturbance of the soil by crop harvesting, dust storms, construction, heavy rainfall, etc., the arthroconidia become airborne and can be inhaled by animal or human hosts. Once inhaled, arthroconidia begin to enlarge and form round spherules in the lung that have thick chitin walls.⁴ Spherules represent the parasitic stage of the fungus. Spherules continue to enlarge and undergo endosporulation. Once the spherule reaches 60-80µm in size, it ruptures, releasing hundreds of endospores into the surrounding tissue. Each individual endospore goes on to form a new spherule within approximately 3 days if not phagocytized by neutrophils and macrophages.^1,5 The parasitic stage may be propagated in this manner indefinitely. Alternatively, endospores may enter the blood or lymphatic vessels and become dispersed to distant sites in the body, resulting in systemic infection.⁴

Epidemiology

C. immitis is endemic to the Lower Sonoran life zone, which includes hot, arid regions of the southwestern United States, northern Mexico, and parts of Central and South America. An outbreak in the San Joaquin Valley of California earned the disease the name of “Valley Fever”.^6,7 Increased numbers of infections are reported in the fall and winter, after crop harvesting and when strong winds commonly disturb the soil and disseminate arthroconidia.^5,8 Infection is most commonly reported in dogs and people, and serologic surveys indicate that most dogs and people living in these areas have been exposed to the organism. Exposure commonly results in subclinical infection or mild respiratory disease, while subsets of the population may be predisposed to more serious respiratory disease or systemic infection.^6,9

Risk Factors

Because C. immitis is limited to certain geographical areas, only animals and people that reside in or have a history of travel to those areas may be affected. The exposure may have been recent, or may have occurred up to years earlier, with the infection remaining dormant until the time of presentation.⁶

Risk factors for infection with C. immitis have been identified in both dogs and humans. Butkiewicz et al. discovered that dogs who spend more time outdoors, have access to large amounts of roaming space, and take frequent walks in the desert are at an increased risk for infection compared to dogs who spend most of their time indoors, are confined to small areas when outdoors, and who take walks on sidewalks. Outdoor dogs were 4.9 times more likely to become infected than dogs that were primarily confined indoors, and seropositive dogs were 6.2 times more likely to have more than one acre of roaming space than seronegative dogs. Surprisingly, there was no association between frequent digging and risk of infection.¹ Butkiewicz et al. reported no significant association between demographic factors, including breed, sex, and neuter status, while others have found that large breed males have an increased risk for infection. This finding may be due to the increased likelihood of these dogs being kept outdoors for extended periods of time.³ While there may be no breed predisposition for infection, Boxers and Doberman Pinschers appear to be more likely to develop severe infections than other breeds. Additionally, in dogs, risk of infection increases with increasing age up until young adulthood, while mature animals may develop immunity to infection.^1,3

In humans, infection occurs in all age groups, with the very young or very old at an increased risk for severe disease. Non-caucasian race is a predictor for developing disseminated disease, with African Americans more likely to develop dissemination to bone and Filipinos more likely to develop cutaneous or central nervous system dissemination. Males are more often infected than females, with the exception of women in the third trimester of pregnancy or who have recently given birth.^3,10 Additionally, any underlying condition causing immunosuppresion (HIV infection, neoplastic disease, immunosuppressive drug administration, etc.) also increases the risk for infection and dissemination.^3,5,10

Clinical Signs

C. immitis received its name based on the round shape of the spherules, which resemble coccidia and the early belief that all cases resulted in serious infection (immitis).¹⁰ It is now known that infection more often causes only an asymptomatic or mild respiratory disease in both animals and humans, with more severe or disseminated cases resulting in the minority of infections.

Dogs: In cases of mild respiratory infection, dogs may present with a dry harsh cough, resulting from tracheobronchial lymphadenomegaly or diffuse interstitial pulmonary disease, or with a moist productive cough, if the alveoli are affected. If the pulmonary disease is advanced, generalized pneumonia and more severe respiratory signs may be present. Fever, weight loss, and inappetance are commonly seen with the respiratory form.^6,8 In cases of systemic infection, the clinical signs are referable to the sites of dissemination. Dissemination may occur with or without respiratory signs. In dogs, spread to the bones of the appendicular skeleton is common, and lameness with or without painful bone swellings may be present (Figure 1).⁴ Other common sites of dissemination include the lymph nodes, skin, liver, spleen, central nervous system and, less frequently, the eye and myocardium. Spread to these sites may be accompanied by generalized lymphadenomegaly, ulcerated nodules or draining tracts in the skin, cranial or paraspinal hyperesthesia, seizures, ocular abnormalities, or signs of left-sided heart failure due to restrictive pericarditis, respectively. Rarely, direct injection of spores through the skin can result in a localized, self-limiting granulomatous lesion.^3,4,6,11

Figure 1. Left: Normal canine scapula. Right: Proliferative bony changes in a canine scapula caused by C. immitis dissemination. (© Noah's Arkive, University of Georgia)

Cats: Cats are less frequently affected than dogs. When infected, disseminated disease is less likely to occur; however, dissemination to the subcutaneous tissues occurs more often in cats than dogs. Subcutaneous masses, abscesses, and chronic draining lesions are frequently observed.¹¹ Due to the initial lack of symptoms, cats are often not presented for veterinary attention until dissemination has already occurred.⁴

Humans: The majority of human cases (60%) result in asymptomatic infection. Approximately 35% of people exhibit respiratory signs that range from mild flu-like symptoms to overt pneumonia. Disseminated disease occurs in 5-10% of cases, with race, gender, and immune status affecting susceptibility to development of systemic disease.^5,8 It is thought that dissemination occurs via the blood and lymphatic vessels, with common sites of extrapulmonary dissemination including the skin, lymph nodes, bone, and meninges. Less frequently reported sites include the pericardium, liver, larynx, and prostate.^10,12,13 In cases of systemic disease, symptoms are referable to the affected organs.

Diagnosis

Diagnosis of coccidioidomycosis may be difficult due to the chronic nature of the disease and the spectrum of nonspecific clinical signs that could also be seen with other infectious, inflammatory, neoplastic, or immune-mediated conditions.⁸ Clinical signs, serum biochemistry analysis, radiographs and other advanced imaging modalities, and serology can be helpful in making a diagnosis, but organism identification by cytology, histopathology, or culture is the only way to make a definitive diagnosis.⁴ The diagnosis is further complicated by the high portion of the population that sustains infection without clinical disease; therefore, presence of the organism may not mean that it is directly responsible for clinical signs observed.

Laboratory findings: In dogs, common CBC abnormalities include the combination of a mild normocytic, normochromic nonregenerative anemia, a mature neutrophilia, and a monocytosis. Hyperfibrinogenemia is sometimes present. The most consistent findings are present in the serum biochemical analysis, and include hypoalbuminemia with hyperglobulinemia. Mild hypercalcemia is sometimes seen and is believed to be a result of the chronic granulomatous inflammation that accompanies coccidiomycosis infection.¹⁴ Activated macrophages that define granulomatous inflammation have been known to spontaneously produce calcitriol, a form of vitamin D, that results in hypercalcemia.¹⁴ No specific changes are seen on urinalysis. These findings are nonspecific and reflect chronic inflammation typical of any type of chronic granulomatous disease; however the findings of hyperglobulinemia and monocytosis in dogs from endemic areas is highly suggestive of disease and a definitive diagnosis should be pursued. Findings are even less specific in cats, and clinicopathologic data may not be helpful in reaching the diagnosis.^3,4,8

Diagnostic imaging: Thoracic radiographs are an integral part of the diagnostic workup for coccidioidomycosis, as pulmonary lesions may be identified even in asymptomatic cases. Interstitial pulmonary infiltrates are the most common findings, and may be diffuse or, more rarely, nodular in appearance. Hilar lymphadenopathy is commonly recognized on radiographs. Less frequent findings include mineralization of airways, pleural thickening, and pleural effusion. These findings are not specific for coccidioidomycosis and may be found with other fungal or neoplastic diseases.^3,8 Radiographs and advanced imaging techniques (CT, MRI) can be useful in identifying disseminated disease in other parts of the body, particularly the appendicular skeleton or CNS. Ultrasound is frequently used to evaluate abdominal organs and to guide sample collection for cytology, biopsy, or culture.⁴

Gross Pathology: Multiple or solitary pulmonary nodules, along with enlarged hilar lymph nodes, are commonly found with the respiratory form of coccidiomycosis (Figures 2 and 3). Consolidated lung lobes and pleural effusion may also occur.⁴ These gross findings are similar to other fungal diseases and even some metastatic neoplasms. Multiple suppurative to caseous nodules can be found in a variety of organs with disseminated disease (Figure 4).

Figure 2. Large pulmonary granulomas in a horse with C. immitis infection. (© Noah's Arkive, University of Georgia)	Figure 3. Multifocal pulmonary granulomas in an alpaca. (© Noah's Arkive, University of Georgia)

Figure 4. Multifocal hepatic granulomas caused by disseminated C. immitis infection (same alpaca as Figure 3). (© Noah's Arkive, University of Georgia)

Cytology and Histopathology: Identification of the characteristic spherules by cytology and histopathology is the most common method for diagnosing C. immitis infection. Cytologic preparations may include tissue aspirates, transtracheal wash or bronchoalveolar lavage samples, joint fluid, or cerebrospinal fluid. Histopathology may be performed on biopsies of any affected tissue. The spherules of C. immitis are large and range from 20-200µm in diameter, depending on the stage of development. They have a thick, refractile double wall that, in mature forms, encases many endospores (Figure 5). The cell wall often collapses and shrinks during processing of the sample, resulting in a distinct folding pattern. Less frequently, free endospores measuring 2-5µm in diameter can be seen in the surrounding tissue (Figure 6).^4,15 The large size of spherules, lack of budding, and presence of endospores help to distinguish C. immitis from other fungi (Blastomyces, Cryptococcus, Histoplasma, Cokeromyces). On histopathology sections, spherules are often surrounded by epithelioid macrophages mixed with smaller numbers of neutrophils and lymphocytes (Figure 7). The inflammatory reaction is greatest around free endospores, with increased numbers of neutrophils and lymphocytes. The organisms are usually well visualized with H&E stains, but due to the sometimes low number present, special stains for fungal glycogen components (PAS, GMS) can aid in identification by staining the thick cell wall.² In the absence of organisms, chronic active pyogranulomatous inflammation is highly suspicious, but not pathognomonic for infection. Other fungal and mycobacterial infections may produce similar lesions.³

Figure 5. Pleural effusion in a dog with C. immitis infection. A large (60 μm), thick-walled Coccidioides spherule containing numerous endospores is present (arrow). The spherules and endospores of Coccidioides stain blue or purple with the Romanowsky-type stains used in cytology. (© Noah's Arkive, University of Georgia)	Figure 6. Lymph node impression smear from a wallaby containing numerous small (2-5 μm) endospores of C. immitis (arrow).

Figure 7. Histologic section of a subcutaneous abscess in a cat. A Coccidioides spherule (arrowhead) is surrounded by numerous degenerate neutrophils (long arrow) and macrophages (short arrow). The spherules and endospores of Coccidioides stain pink with the H&E stain used in histology. (© Noah's Arkive, University of Georgia)

Serology: Serology can be an effective means to diagnose infection with C. immitis, however there does not appear to be a direct correlation between titer and severity of clinical signs or extent of disease. Furthermore, negative serologic test results have been obtained from animals that were known to be infected.^6,8 The most common serologic tests performed are the agar gel immunodiffusion (AGID) tests for IgM against the tube precipitin (TP) antigen and for IgG against the complement fixing (CF) antigen of C. immitis. Other tests, including ELISA and latex agglutination tests for IgM, have recently become available; however, they have not been fully evaluated for use with animal serum.⁴ Serologic tests results should be interpreted in light of the history, clinical signs, and other diagnostic tests.

Treatment and Prognosis

Due to the high variability in severity and extent of disease, no standard treatment protocol has been defined. Some patients may recover without any treatment, while others may die after aggressive medical treatment.³ Therapy may be avoided in patients that have only mild respiratory signs. In patients with more severe pulmonary or systemic disease, long-term systemic antifungal therapy is required. The azole antifungals (ketoconazole, itraconazole, and fluconazole) are the most widely prescribed drugs in veterinary medicine, with amphotericin B used less frequently. The prognosis is highly variable, with an estimated overall recovery rate of 60%.⁶ Patients with mild respiratory signs usually make a full recovery, while those with disseminated disease may die or require medical treatment for the rest of their lives. Some dogs, and many cats, have relapses of disease when therapy is discontinued after apparent clinical resolution.^6,11

Prevention

Because the infectious arthroconidial stage is acquired from the environment and does not form in human or animal tissues, coccidioidomycosis is considered to be a highly infectious but noncontagious disease.^2,6,16 Infection is reportable in California, New Mexico, and Arizona, where the disease is endemic.⁸ The mycelial stage present in soils represents a serious biohazard, and efforts to avoid animal or human exposure during times of increased soil disturbance should be made. Additionally, growth of the mycelial form in culture media can result in significant human exposure. Culture should only be performed by diagnostic laboratories equipped for handling the organism. A veterinarian contracted a fatal infection while performing a post-mortem examination on a horse with disseminated disease. It is thought that transmission occurred in that case by inhalation of endospores that were aerosolized during the procedure.¹⁶ Appropriate precautions should be taken when handling tissues that may be infected.

Based on the fact that natural human infection results in lifelong immunity against respiratory disease, vaccination has been proposed as a method for disease prevention and control.⁷ A killed spherule vaccine has been produced that is effective in preventing infection in mice, but similar vaccines have not proven efficacious in other animals or people. Current research is focusing on the development of purified antigen and recombinant vaccines.6  Until an effective vaccine is developed, prevention of infection is best achieved by avoidance of the soil-borne infective mycelial stage.

References

1. Butkiewicz CD, Shubitz LF, Dial SM: Risk factors associated with Coccidioides infection in dogs. Journal of the American Veterinary Medical Association. Jun 2005; 226 (11): pp. 1851-4.

2. Jones CJ, Hunt RD, King NW: Veterinary pathology, 6th ed. Baltimore, Williams & Wilkins, 1996, pp. 510-512.

3. Heinritz CK, Gilson SD, Soderstrom MJ, Robertson TA, Gorman SC, Boston RC: Subtotal pericardectomy and epicardial excision for treatment of coccidioidomycosis-induced effusive-constrictive pericarditis in dogs: 17 cases (1999-2003). Journal of the American Veterinary Medical Association. Aug 2005; 227 (3): pp. 435-40.

4. Shubitz LF, Dial SM: Coccidioidomycosis: A Diagnostic Challenge, Clinical Techniques in Small Animal Practice, Nov 2005; 20 (4): pp. 220-6.

5. Cox RA, Magee DM: Protective immunity in coccidioidomycosis. Research Immunology. May-June 1998; 149 (4-5) pp. 417-28.

6. Greene, CE: Infectious Diseases of the Dog and Cat, 3rd ed. St. Louis, Elsevier Inc., 2006, pp. 598-608.

7. Xue J, Hung CY, Yu JJ, Cole GT: Immune response of vaccinated and non-vaccinated mice to Coccidioides posadasii infection. Vaccine. 2005; 23: pp. 3535-3544.

8. Johnson LR, Herrgesell EJ, Davidson AP, Pappagianis D: Clinical, clinicopathologic, and radiographic findings in dogs with coccidioidomycosis: 24 cases (1995-2000). Journal of the American Veterinary Medical Association. Feb 2003; 222 (4): pp. 461-6.

9. DiCaudo DJ, Connolly SM: Interstitial granulomatous dermatitis associated with pulmonary coccidioidomycosis. J Am Acad Dermatol 2001; 45: pp. 840-5.

10. Crum NF, Lederman ER, Stafford CM, Parrish JS, Wallace MR: Coccidioidomycosis: A descriptive survey of a reemerging disease. Clinical characteristics and current controversies. Medicine. May 2004; 83 (3): pp. 149-73.

11. Medleau L, Hnilica KH: Small Animal Dermatology: A Color Atlas and Therapeutic Guide, 2nd ed. St. Louis, Elsevier Inc., 2006, pp. 91-92.

12. Arsura EL, Bobba RK, Reddy CM: Coccidioidal pericarditis: a case presentation and review of the literature. International Journal of Infectious Diseases. 2005; 9: pp. 104-9.

13. Yurkanin JP, Ahmann F, Dalkin B: Coccidioidomycosis of the prostate: a determination of incidence, report of 4 cases, and treatment recommendations. Journal of Infection. Jan 2006; 52(1): e19-25.

14. Rohrer CR, Phillips, LA, Ford SL, Ginn PE: Hypercalcemia in a dog: a challenging case. Journal of the American Animal Hospital Association. 2000; 36: pp. 20-25.

15. Latimer KS, Mahaffey EA, Prasse KW: Duncan and Prasse’s Clinical Pathology, 4th ed. Ames, Iowa State Press, 2003, p. 307.

16. Kohn, GJ, Linne SR, Smith CM, Hoeprich PD: Acquisition of coccidioidomycosis at necropsy by inhalation of coccidioidal endospores. Diagnostic Microbiology and Infectious Disease. Aug 1992; 15 (6): pp. 527-30.

Acknowledgement

"Cat Joy" by Debbie Savannah George (Copyright 2007) is from her website dSavannahCREATIVE and is used with permission.

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