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Four 15- to 21-year-old men from Southampton County, Va became ill in March 1988. All had similar clinical signs including fever, cough, and a pulmonary infiltrate on thoracic radiographs. Blastomyces dermatitidis was isolated from sputum or lung tissue from each person.¹

The men had hunted raccoons together at least once weekly from October through February. Hunting was done locally, at night, in wooded, swampy areas. Seven dogs (1 Doberman Pinscher, 6 Coonhounds) were used by the hunters on each occasion.

Four of the 7 hunting dogs became ill at approximately the same time as the hunters. Clinical signs in the dogs included fever, cough, exercise intolerance, and weight loss. Blastomyces dermatitidis was isolated from lung tissue in 3 of the 4 dogs; tissue from the fourth dog was not available for examination. Blastomyces was not isolated from selected soil or vegetation samples obtained from areas where the men and dogs had hunted.¹

All 4 men were treated successfully with amphotericin B, ketoconazole, or a combination of both drugs. The 4 infected dogs were not treated and died.¹

A veterinarian involved in the evaluation of the sick dogs was asked the following questions by the physician who had treated one of the affected men.

Q: Was blastomycosis transmitted from the dogs to the hunters?

A: Not in this case. Transmission of any of the 4 major systemic mycotic agents (Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Cryptococcus neoformans) directly from animals to human beings is extremely rare.^2-5 According to the classification of Schwabe,⁶ these 4 mycotic agents are those that cause saprozoonoses. Saprozoonoses are those zoonoses that require a nonanimal site to serve as either a true reservoir of infection (not merely an optimal growth medium) or as a site for an essential phase of the development of the organism.⁶ The mycotic saprozoonotic organisms are not dependent on human beings or another vertebrate host for survival.

In this situation, the hunters and the dogs were infected from a common environmental source. Failure to isolate the organism from the soil and vegetation is not unusual. The systemic mycotic agents are difficult to isolate from the environment.^7,8 In addition, the men and dogs had traveled over a wide area and a focal source of infection could have been easily overlooked.

Q: What is the life cycle of the 4 major systemic mycotic organisms?

A: Blastomyces, Coccidioides, and Histoplasma are dimorphic fungi.^9-12 In their free-living, mycelial stages, they reside in soil or decaying organic matter and produce spores (conidia, arthroconidia, macro- and microaleuriospores) that are potentially infectious for vertebrates.^9,11 When introduced into a vertebrate host, dimorphic fungi undergo transformation to their respective parasitic forms at 37 C. In this form, they reproduce asexually, either intracellularly or extracellularly, by budding or endosporulation.^10-12 The size of the fungal inoculum and the competence of the immune system of the host determines whether the infection will result in focal infection or disseminated disease.¹²

Although mycelial and pseudomycelial forms of Cr neoformans are rarely encountered, isolations from the environment and animals are almost invariably of the yeast phase.^12,13

Q: What is the environmental distribution of these mycotic organisms?

A: Cryptococcus has a worldwide distribution.^9,10,13-15 The other systemic mycoses have regional environmental preferences based on the optimal growth characteristics of the organisms (Fig 1).^9,12

Figure 1--Areas of highest environmental concentration of the major systemic mycotic diseases found in the continental United States (Adapted from Wolf AM, Troy GC¹².

The concentration of organisms at any locale varies widely within the general areas of endemicity.¹⁶ Alterations in the local environment such as construction, irrigation, and forestry may change a previously nonendemic site into a favorable location for fungal growth.^17,18

Q: What role do animals play in the systemic mycotic diseases?

A: Domestic and wild animals are susceptible, accidental hosts for these pathogens as are human beings; however, the pathogenicity of each of the mycotic diseases varies widely among the animal species.¹⁰ Animals also play a role in the environmental distribution of the systemic mycoses. Coccidioides immitis has an association with rodent burrows because these animals may bring infected soil to the surface during the excavation of their tunnels and because the tunnels themselves provide a favorable microenvironment for the fungus.¹⁴

The growth of both H capsulatum and Cr neoformans is enhanced by the high nitrogen environment furnished by bird and bat excrement.^{6,9,10,14,19-23} Therefore, bird and bat roosting sites (trees, caves) are likely sources of infectious fungal particles.^{9,14,15,19-25} Although the body temperature of most birds is too high to support the growth of mycotic organisms, their primary role is as a mechanical vector to transport the fungi from place to place.^{13,14,18,19,22} Bats can contract histoplasmosis and are biologic as well as mechanical vectors for this organism.^18,19,23

The isolation of B dermatitidis from soil from a beaver lodge led to concern about this species as a possible vector for blastomycosis.²⁶ More recent studies have exonerated the beaver as a source of contagion, but confirm that Blastomyces has a strong association with water and waterways.^7,26 This may be because moist soil, high humidity, and organic matter enhance its growth.^7,26,27

Finally, because most domestic animals have a limited range of exposure to the environment, they are useful as sentinels for epidemiologic study.⁸

Q: How do vertebrates usually acquire these mycoses?

A: Human beings and animals usually acquire these mycoses by inhalation of infectious particles (spores, mycelial fragments, yeast [Cryptococcus only]) from an inanimate environmental source.^{7,9-12,14,16,17,22,24,26,27} Some evidence suggests that Histoplasma infection of the gastrointestinal tract in dogs can develop as a result of ingestion of the fungus; however, considerable controversy about this route of infection still exists.^12,28

Q: What are the usual clinical signs caused by these mycotic agents?

A: Natural infection with B dermatitidis, C immitis, and H capsulatum usually induces disease that is unrecognized.^{10,11,14,16,18-20} If the fungal inoculum is large or the immune system is suppressed, clinical signs may develop, including fever, lethargy, coughing, and dyspnea.^{10,12,17-19,23,27,29} The immune system may limit the infection to the respiratory tract or there may be dissemination to other body organs. The signs of illness with disseminated disease may be vague and diverse. Each organism has specific tissue tropisms and preferred sites for dissemination. Blastomyces frequently affects the eye, skin, and bone, Coccidioides targets bone, and Histoplasma often affects the liver, intestines, lymph nodes, and bone marrow.^7,10-12,29

The lung is believed to be the usual portal of entry for Cr neoformans; however, this organism rarely causes clinical pulmonary disease.^{13-15,19,23,24} Most clinical infections in human beings and dogs involve the CNS, causing signs of encephalitis and meningitis.^{9,12-14,19,22,23,25,30} Cryptococcosis in the cat may involve the CNS, but most frequently affects the nasal cavity, causing sneezing, nasal discharge, and facial swelling.^9,12,23 Infection with Cr neoformans may also cause subclinical disease.^19,23

Q: Are there other routes for infection and what clinical signs would develop in human beings infected through these other routes?

A: Naturally developing disease resulting from direct cutaneous inoculation with the mycelial form of these organisms is rare.^{11,18,27,31-33} A few cases of cutaneous inoculation resulting from laboratory accidents have also been reported.^14,31,33,34 Transcutaneous infection usually results in disease that is limited to the skin and regional lymph nodes.^{11,15,24,31-35}

The potential for cutaneous infectivity is low among the parasitic forms of these organisms. Percutaneous infection is most likely with the yeast phase of B dermatitidis. Three human beings have contracted primary cutaneous blastomycosis as a result of bite wounds inflicted by dogs affected by B dermatitidis.^2-5 It was believed that the sputum from these dogs was heavily contaminated with Blastomyces organisms originating from the respiratory tract.^3,36 Several pathologists have incurred infection with Blastomyces while handling infected tissues during postmortem examinations.³⁷ Percutaneous infection by the parasitic phase of Coccidioides or the yeast phase of Histoplasma or Cryptococcus is rare.^{13,15,18,24,35,38}

Q: How does one confirm systemic mycotic infection?

A: Systemic mycoses is usually confirmed by identification of the fungal organisms in affected tissues.^{6,8-10,13,18,19,26,39} Serologic testing to detect antibody generated against Blastomyces and Histoplasma antigens is often used in human beings, but is unreliable in animals.^{6,7,9,12,18,20,26,29,39} Serologic testing for coccidioidomycosis is helpful as a diagnostic tool in people and animals and can be used to monitor the progress of treatment.^12,16,39 Latex agglutination cryptococcal antigen titers can also be used for diagnosis and to follow a patient's response to antifungal treatment.^12,13,39

Q: What are important risk factors for contracting these systemic mycoses?

A: Natural exposure in an endemic area is the most important risk factor. Specific occupations and activities may also contribute to increased exposure to the organisms. Earth-moving activities such as road construction, agriculture, or archaeologic excavation are frequently associated with infection by C immitis.^11,14,16 Farmers, gardeners, military personnel, and spelunkers have an increased risk of contracting histoplasmosis.^14,18,29,40 Group exposures to H capsulatum have also occurred in people occupying buildings or felling trees used as bird roosts.^14,29 Blastomycosis does not have an association with any specific occupation, but develops most frequently in people engaging in outdoor activities, particularly along waterways.^7,26,27,32

One might expect a high number of cases of cryptococcosis in people working closely with pigeons or other birds because of the association of Cryptococcus with bird guano.^21,22 Surprisingly, although those people have serologic evidence of high exposure, clinical cryptococcosis is no more frequent among those people than in the general population.¹³ Although no specific activities are associated with the development of clinical cryptococcosis, exposure to a high density of aerosolized Cryptococcus organisms in bird guano should be avoided.

Mycologists and other workers handling mycelial cultures of the systemic mycotic organisms are at risk for laboratory-acquired infection.^13,14,16,27 The spores or mycelial fragments of C immitis and H capsulatum are particularly volatile and easily become airborne.^13,16 Blastomyces spores are less dangerous.¹³ Old, dry cultures are a greater hazard than those with new growth. Mycelial cultures of all of these organisms should be tightly sealed and handled only by experienced personnel in a facility qualified to work with class-III infectious agents.^14,16

In one unusual report,⁴¹ hospital-acquired infection occurred in several physicians and nurses who apparently inhaled spores from C immitis growing on the surface of a plaster cast covering the leg of a patient with a draining wound.

The systemic mycotic agents are more likely to cause clinical disease in people that are immunocompromised.^{10,14,15,29,30,35,42-44} This includes people receiving immunosuppressive drugs (eg, antirejection drugs in transplant patients, chemotherapy in cancer patients) and pregnant women.^22,29,30,35 Human beings with acquired immunodeficiency syndrome caused by human immunodeficiency virus have a high prevalence of systemic mycotic disease.^29,43,44 At this time, no immune deficiency has been definitively identified in animals affected with these mycotic diseases.²⁰

Q: What is the recommended treatment for the systemic mycotic diseases?

A: Animals and human beings with blastomycosis, histoplasmosis, and coccidioidomycosis usually are treated with one of the orally administered azole antifungal drugs (ketoconazole, itraconazole) alone or in combination with IV administration of amphotericin B.^{7,12,19,23,26,29,31,32,45} A combination of amphotericin B and 5-fluorocytosine is the treatment of choice for cryptococcosis in human beings^13,19,24,42; however, some of the newer azole antifungal drugs also are associated with good responses.^15,35,46 Feline nasal and cutaneous cryptococcosis have been successfully treated with ketoconazole alone.¹²

Primary cutaneous disease resulting from direct transcutaneous inoculation usually remains localized and may regress without treatment^{12,27,31,37,38}; however, primary cutaneous disease is rare and all cutaneous lesions should be assumed to be the result of dissemination until proven otherwise.^12,24,43,47 Further, dissemination from a primary inoculation site is possible, particularly in an immunocompromised host.^31,37 Therefore, antifungal chemotherapy has been recommended for all people with confirmed infection with any of the systemic mycotic agents.

Q: How can these diseases be prevented?

A: There are no effective immunoprophylactic measures available to prevent infection with these fungal agents.^20,27 Prevention consists of avoiding exposure to environmental sites likely to harbor the fungus. Spot soil disinfection with 3% formalin may be attempted if local areas of fungal contamination are identified.^10,18,23

When managing infected people or animals, one should avoid direct cutaneous inoculation and exposure to infected materials during surgery or necropsy examinations.⁹ Dressings covering a draining fungal lesion should be changed frequently to prevent mycelial growth and sporulation on the surface of the bandages. Fungal cultures from patients suspected of having systemic mycotic infection that contain fluffy, white mycelial growth should be sealed and handled with caution.¹⁶

References

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38. Castillo JLM, Negro GD, Heins-Vaccari E, et al. Primary cutaneous cryptococcosis. Mycopathologia 1986; 96:25-28.

39. Sarosi GA, Armstrong D, Davies SF, et al. Laboratory diagnosis of mycotic and specific fungal infections. Am Rev Respir Dis 1985; 132:1373-1379.

40. Hunt PJ, Harden TJ, Hibbens M, et al. Histoplasma capsulatum. Isolation from an Australian cave environment and from a patient. Med J Aust 1984; 141:280-283.

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42. Dismukes WE, Cloud G, Gallis HA, et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared to six weeks. N Engl J Med 1987; 317:334-341.

43. Barton EN, Roberts WE, Ince AL, et al. Cutaneous histoplasmosis in the acquired immunodeficiency syndrome--a report of three cases from Trinidad. Trop Geogr Med 1988; 40:153-157.

44. Miller SJ. Cutaneous cryptococcosis resembling molluscum contagiosum in a patient with acquired immunodeficiency syndrome. Cutis 1988; 41:411-412.

45. Graner A, Arathoon E, Stevens DA. Initial experience in therapy for progressive mycoses with itraconazole, the first clinically studied triazole. Rev Infect Dis 1987; 9(Suppl):S77-S85.

46. Perfect JR, Savani DV, Durack DT. Comparison of itraconazole and fluconazole in the treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrob Agents Chemother 1986; 29:579-583.

47. Dickinson A, Tschen JA, Wolf JE Jr. Coccidioidomycosis with cutaneous involvement. South Med J 1984; 77:1464-1465.