Dimorphic fungi

Organism	Distribution	Diseases	Treatment
Blastomyces	eastern US and Canada, with some reported in Africa	pulmonary infection, verrucous skin lesions, osteomyelitis, CNS infection	itraconazole (with amphotericin B induction if severe)
Coccidioides	southwestern US and parts of South and Central America	pulmonary infection, verrucous skin lesions, osteomyelitis, CNS infection	fluconazole (with amphotericin B and flucytosine induction if severe)
Histoplasma capsulatum	worldwide, including eastern North America, Central and South America, sub-Saharan Africa, and parts of Southeast Asia	pulmonary infection, CNS infection	itraconazole (with amphotericin B induction if severe)
Paracoccidioides brasiliensis	South America	pulmonary infection	itraconazole (with amphotericin B induction if severe)
Sporothrix schenckii	essentially worldwide	nodular lymphangitis	itraconazole
Talaromyces marneffei	Southeast Asia	disseminated (common in advanced HIV), pulmonary infection, abdominal abscess, skin lesions, osteomyelitis	amphotericin B induction followed by itraconazole

Background

Microbiology

• Broad category of fungi that exist in a mold form at lower temperatures in the environment, and a yeast form at higher temperatures in the host body
• Cryptococcus does exhibit dimorphism, though it is predominately yeast and its dimorphism is not likely related to disease
• Often referred to as endemic fungi based on their geographic niches
• Includes the following genera and species:
  • Blastomyces, including Blastomyces dermatitidis complex (Blastomyces dermatitidis and Blastomyces gilchristii), helices, silverae, parvus
  • Histoplasma capsulatum (var. capsulatum and var. duboisii)
  • Coccidiodes, including Coccidioides immitis and Coccidioides posadasii
  • Paracoccidioides, including Paracoccidioides brasiliensis and Paracoccidioides lutzii
  • Talaromyces marneffei
  • Emergomyces, including Emergomyces pasteurianus, Emergomyces africanus, Emergomyces orientalis, Emergomyces canadensis, Emergomyces europaeus
  • Sporothrix complex (Sporothrix brasiliensis, Sporothrix schenckii, Sporothrix globose, Sporothrix luriei)

Epidemiology

• Endemic dimorphic fungi are widely distributed1

Histoplasmosis

Histoplasmosis

• High-endemic areas include Ohio and Mississippi river valley systems, but also in Central and South America
  • However, 12-20% of cases in US occur outside of endemic areas
  • In Canada, mostly along St. Lawrence seaway and Great Lakes drainage
• More recently, cases have been diagnosed in Alberta and Saskatchewan
• Also found in Asia and Africa, throughout, with var. duboisii in West Africa (mostly skin and soft tissue disease)
• Associated with soil contaminated by bird or bat guano

Coccidiomycosis

Coccidiomycosis

• More common in southwestern US, especially California and Arizona (but up to Washington state), as well as parts of South and Central America
  • Concentrated heavily in San Joaquin Valley in California
• Present in soil
• High-risk activities: construction, military maneuvers, earthquakes/landslides, armadillo hunting, prisoners from other parts of the US that are incarcerated in California

Blastomycosis

Blastomycosis

• Found mostly in eastern North America
  • In Canada, found in northwestern Ontario, Quebec, Manitoba, and Saskatchewan
    • Kenora is the hotspot in Canada
• More common in wooded areas, damp soil, and near waterways
• High-risk activities include excavation and construction

Emergomycosis

• Different species found worldwide, including Emergomyces canadensis in Saskatchewan, Colorado, and New Mexico
• More common in HIV patients or other immunocompromised

Clinical Manifestations

Histoplasmosis

	Acute Pulmonary	Cavitary and Chronic Pulmonary	Progressive Disseminated
Clinical	usually asymptomatic or mild; can have non-pleuritic chest pain from mediastinal or hilar lymphadenopathy; can have rheumatic features or pericarditis	8% develop fibrocavitary disease, associated with underlying COPD
Immunology	>90% positive skin test, 20% urine antigen	75-95% antibodyes, 40% urine antigen	60-90% urine antigen
Culture	<25% positive	5-70% positive (more likely if cavitary)	50-70% positive

Blastomycosis

• Inhalation is main portal of entry
• Incubation 3 weeks to 3 months
• In outbreaks, 50% of exposed developed symptoms
• Primarily presents with pulmonary blastomycosis with influenza-like illness, acute pneumonia, ARDS, or chronic pneumonia
• Skin is most common extrapulmonary site, but can also infect bone and prostate
• CNS infection is rare

Coccidiomycosis

• Asymptaomtic common in 60%
• Early pulmonary infection
  • Mild
  • Valley fever, including arthralgias and erythema nodosum
• Extrapulmonary dissemination
  • More common in African Americans

Emergomycosis

• Cutaneous disease in immunocompromised patients, especially advanced HIV
• Can also cause pulmonary disease, extrapulmonary disease, or disseminated

Diagnosis

• Notify laboratory if a risk group 3 organism is suspected
• For blood cultures, the isolator system is preferred to BacTAlert
• Media
  • Brain-heart infusion with sheep blood plus antibacterials is preferred
  • Cycloheximide can be used to prevent growth of saprophytic molds (always with one plate without)
  • Incubate at 30ºC to enhance growth of mold forms
  • Incubated for 3 weeks for fungi in general, but should be extended to 4 weeks for dimorphic fungi
    • Coccidioides is the fastest-growing, within 3 to 5 days on SAB, and can grow on chocolate and sheep's blood agars

Organism	Findings on Microscopy
Histoplasma	intracellular 2-4 μm yeast-like cells in macrophages, may have narrow-based budding
Blastomyces	8-15 μm yeast-like cells with broad-based budding, refractile thick cell wall, but early spherules can be confused with Coccioides
Coccidioides	spherules are thick-walled, 10-80 μm with endospores; alternating barrel-shaped arthroconidia in mycelial form
Marneffei	divides by binary fission
Emergomyces	2.5-5 μm small yeast form with narrow-based budding; septate hyphae with conidiophores at right answers, with conidia clustered in florettes of 2 to 3 conidia

EORTC Definition2

• Proven invasive fungal disease
  • Histopathology or direct microscopy of sterile material of specimens obtained from an affected site showing the distinctive form of the fungus, or
  • Recovery by culture of sterile material of the fungus from specimens from an affected site, or
  • Blood culture that yields the fungus
• Probable invasive fungal disease
  • Requires clinical features and mycologic evidence, but host does not have to be immunocompromised for dimorphic or endemic fungi
  • Host factors: not applicable
  • Clinical features: evidence for geographical or occupational exposure (including remote) to the fungus and compatible clinical illness
  • Mycological evidence:
    • Histoplasma or Blastomyces antigen in urine, serum, or body fluid
    • Antibody to Coccidioides in CSF or 2-fold rise in 2 consecutive serum samples

Prevention

Laboratory Safety

• Many are risk group 3 and need to notify lab if suspected
• Opening the plates outside of a BSC is one of the highest risk actions