Systemic Fungal Pathogens​-69

What is thermal dimorphism in systemic fungal pathogens?

Thermal dimorphism refers to the ability of fungi to exist as a mold form at 25–30°C and convert to a yeast or spherule form at 37°C (in the host).

What are characteristics of systemic endemic fungal pathogens?

• Primary pathogens

• Facultatively parasitic (primarily soil organisms)

• Cause systemic mycoses beginning with primary lung infection, followed by possible dissemination to other organs/tissues

• Are endemic to specific geographic regions

What fungi are systemic endemic pathogens that exhibit thermal dimorphism?

• Blastomyces dermatitidis

• Coccidioides immitis, C. posadasii

• Histoplasma capsulatum (var. capsulatum, var. duboisii)

• Paracoccidioides brasiliensis

• Talaromyces (Penicillium) marneffei

Which systemic dimorphic fungi are also major opportunistic pathogens?

• Histoplasma capsulatum

• Coccidioides immitis, C. posadasii

• Talaromyces marneffei

What are the geographic distributions of Coccidioidomycosis, Blastomycosis, and Histoplasmosis in the U.S.?

• Coccidioidomycosis: Mostly found in the Southwestern U.S., along a route from California to Texas

• Blastomycosis: Found in a vertical zone from central Kansas straight north and south, including the Mississippi and Ohio River valleys

• Histoplasmosis: Endemic throughout all of Kansas, most of Texas, and widely present in the Ohio and Mississippi River valleys

might delete if covered lateer

Where is Blastomyces dermatitidis found, and what is its environmental source?

Blastomyces dermatitidis is found mostly in the Ohio and Mississippi River basins, Great Lakes, and Southeastern U.S., overlapping with histoplasmosis regions. It resides in decaying plant material, leaf litter, rotting wood, and soil.

How does Blastomyces dermatitidis transmission occur?

Transmission typically occurs from plant material to dogs to humans. The mold form is saprobic, while the yeast form is parasitic.

What is the morphology of Blastomyces dermatitidis in mold and yeast phases?

• Mold phase: Oval conidia on long or short terminal hyphal branches

• Yeast phase (in tissue): Large, thick-walled, non-encapsulated cells that reproduce by broad-based budding (blastoconidia formation)

What species is especially susceptible to Blastomyces dermatitidis?

Dogs are highly susceptible, with infection rates up to 10 times higher than in humans.

what molecole Blastomyces dermatitidis transmitted and what factors affect disease severity?

Transmission occurs via inhalation of conidia.
Severity depends on the extent of exposure and the host’s immune status.

What are the pulmonary manifestations of blastomycosis?

• May be asymptomatic or present as a mild, flu-like illness

• Severe cases resemble bacterial pneumonia with acute onset, high fever, lobar infiltrates, and cough

• Can cause ARDS (acute respiratory distress syndrome) with high fever, diffuse infiltrates, and respiratory failure

• May show perihilar mass lesions on imaging

How does blastomycosis compare to histoplasmosis and coccidioidomycosis in severity?

Blastomycosis is less likely to self-resolve, even in acute cases, so treatment is typically required regardless of severity.

What are the features of subacute or chronic blastomycosis?

Subacute/chronic blastomycosis can mimic tuberculosis or lung cancer, showing persistent pulmonary symptoms and infiltrates.

What are the extrapulmonary manifestations of blastomycosis?

Back:
Extrapulmonary dissemination may occur in:

• Skin (can mimic squamous cell carcinoma)

• Bones, CNS, and other organs

Is blastomycosis common in immunocompromised patients?

No — blastomycosis is uncommon in AIDS or other immunocompromised individuals.

What are the features of classic cutaneous blastomycosis?

Classic blastomycosis presents with chronic cutaneous lesions, often located on the face, scalp, neck, or hands.
Note: These lesions can mimic squamous cell carcinoma.

How is blastomycosis diagnosed?

k:

• Detection of broad-based budding yeasts in clinical specimens (e.g., lung, sputum, CSF, skin)

• Culture demonstrating thermal dimorphism (mold at room temp, yeast at 37°C)

• Exoantigen testing may be used (though specificity can vary)

How is blastomycosis treated?

• Amphotericin B (lipid formulation) for severe or disseminated disease

• Itraconazole or other azoles for milder cases

• In immunocompromised patients, long-term itraconazole is used to suppress relapses

What causes coccidioidomycosis and where are the species found?

Coccidioidomycosis is caused by two species:

• Coccidioides immitis – found in California

• C. posadasii – found outside California, including the Southwestern U.S. and Mexico

Where is Coccidioides found in the environment, and what enhances its growth?

Coccidioides is found in soil, especially where bat and rodent droppings are present.
Growth is enhanced during rain-drought cycles:

• Rain promotes fungal growth in nitrogen-rich soil

• Drought and wind promote aerosolization of infectious arthroconidia

When is the risk of exposure to Coccidioides highest?

Exposure to arthroconidia is greatest in late summer and fall, especially under dusty conditions.

What are the morphological forms of Coccidioides in the environment and in tissue?

• Mold phase (saprobic): Produces barrel-shaped arthroconidia and disjunctor cells

• Tissue phase (parasitic): Develops into spherules filled with endospores

How does the immune system respond to Coccidioides infection?

Coccidioides infection triggers a delayed-type hypersensitivity (DTH) response.
The presence of erythema nodosum ("desert bumps") and arthritis is considered a good prognostic sign (Kaplan).

How is Coccidioides transmitted and how common is infection in endemic areas?

• Infection occurs via inhalation of arthroconidia

• Coccidioides is highly infectious

• In endemic areas, >80% of the population may have positive skin tests, indicating exposure

What are common clinical presentations of pulmonary coccidioidomycosis?

• Most infections are asymptomatic or self-limiting

• Symptoms may include cough, chest pain, fever, dyspnea, pleuritic pain, and lung lesions (which may calcify during healing)

• Skin signs: erythema nodosum (“desert bumps”), erythema multiforme

What happens after spherule rupture in coccidioidomycosis?

Rupture of spherules can lead to a pyogenic (pus-producing) reaction and inflammatory damage.

What is the rate and pattern of dissemination in coccidioidomycosis?

• Dissemination occurs in ~1% of cases, often affecting skin, meninges, and bones

• Risk of dissemination is higher in Filipino, African American, Native American, and Hispanic populations, the immunosuppressed, and during the third trimester of pregnancy

Why is coccidioidomycosis called “the great imitator”?

It presents with a wide variety of lesions that can mimic tuberculosis, syphilis, and other diseases, making diagnosis challenging.

What are alternative names for coccidioidomycosis?

Coccidioidomycosis is also known as:

• Coccidioidal granuloma

• San Joaquin Valley Fever

Why is pregnancy a risk factor for coccidioidomycosis?

Pregnancy, especially in the third trimester, is associated with a higher risk of dissemination due to immune modulation.

What is erythema nodosum in coccidioidomycosis?

Erythema nodosum is an immunologic skin response to the fungus, often seen in Caucasian women. It is a good prognostic sign indicating effective immune response.

What does dissemination of pulmonary coccidioidomycosis look like?

It may present as a large, superficial, ulcerated plaque, typically resulting from extension of the pulmonary infection.

How is coccidioidomycosis diagnosed?

• Microscopy: Direct examination of sputum, exudates, or tissue to identify spherules

• Culture: Demonstrates dimorphism, but requires caution as it is highly infectious

• Serologic testing can support diagnosis

How is primary coccidioidomycosis treated?

• In healthy individuals: Often no antifungal treatment needed

• In immunocompromised patients: Amphotericin B, followed by azole prophylaxis for ≥1 year

How is chronic coccidioidomycosis treated?

• Azole antifungals (e.g., fluconazole) for ≥1 year

• Amphotericin B may also be used

• Surgical intervention (e.g., lung resection) may be necessary

How is meningeal coccidioidomycosis treated?

• Fluconazole or other azole antifungals

• Amphotericin B may be used in refractory cases

What are the risk factors for severe or disseminated coccidioidomycosis?

• Age: Highest risk in infants and the elderly

• Sex: Male patients are at higher risk

• Genetics: Risk hierarchy — Filipino > African American > Native American > Hispanic > Asian

• Serum complement fixation (CF) antibody titer: High risk if >1:32

• Pregnancy: Especially late pregnancy and postpartum

• Skin test: Negative skin test indicates poor cell-mediated immunity

• Immunosuppression: From malignancy, chemotherapy, steroid use, or HIV infection

What are the varieties and basic biology of Histoplasma capsulatum?

There are two varieties:

• Histoplasma capsulatum var. capsulatum

• Histoplasma capsulatum var. duboisii
  They are indistinguishable in culture and exhibit thermal dimorphism.

What is the saprobic (mold) phase of Histoplasma capsulatum?

At 25°C, H. capsulatum grows as a hyaline mold:

• Produces tuberculate macroconidia (conidia with spiked walls)

• Also forms small microconidia

What is the parasitic (yeast) phase of Histoplasma capsulatum?

At 37°C (in tissue), it exists as an intracellular budding yeast, commonly found inside macrophages.

Where is Histoplasma capsulatum commonly found, and how is infection acquired?

Found in the Ohio and Mississippi River valleys, Mexico, Central and South America.
It thrives in nitrogen-rich environments like bird (guano) and bat droppings (e.g., chicken coops, caves).
Infection occurs through inhalation of microconidia or hyphal fragments

What is the typical presentation of pulmonary histoplasmosis?

• Mostly asymptomatic after low-intensity exposure

• Can cause flu-like illness: fever, cough, myalgia, chest pain

• May include hilar and mediastinal lymphadenopathy and pulmonary infiltrates

What severe or chronic pulmonary complications can result from histoplasmosis?

• ARDS (acute respiratory distress syndrome)

• Bronchial obstruction

• Pericarditis, arthritis, arthralgias

• Mediastinal fibrosis

• Chronic histoplasmosis: pulmonary cavities and fibrosis

What are signs of disseminated histoplasmosis?

• Oral ulcers, hepatosplenomegaly

• Possible involvement of heart, CNS, bone marrow

• Bone marrow involvement can cause anemia, leukopenia, and thrombocytopenia

Who is at greatest risk for fulminant disseminated histoplasmosis?

AIDS patients and the immunosuppressed are at highest risk.
Dissemination can mimic septic shock and be fatal within days if untreated.

How can histoplasmosis be confused with other diseases?

Back:
Histoplasma can cause granulomatous lesions, which may resemble tuberculosis, sarcoidosis, or coccidioidomycosis.
Differentiation relies on identifying thin-walled yeast forms in tissue.

What does Histoplasma capsulatum var. duboisii cause, and where?

Causes predominantly skin and bone lesions, and is geographically restricted to tropical areas of Africa.

How is histoplasmosis diagnosed?

• Direct microscopy and histopathology often show intracellular yeasts

• Serology: detection of antigens and antibodies, though antibody tests may be negative in immunocompromised patients

• Culture (e.g., from sputum, blood) with confirmation via thermal dimorphism—note: cultures are highly infectious and require biosafety precautions

What are the typical exposure histories for coccidioidomycosis, blastomycosis, and histoplasmosis?

• Coccidioidomycosis: Exposure during sandstorms, construction, or military exercises—especially in dry periods following rain

• Blastomycosis: Outdoor activity near waterways

• Histoplasmosis: Exposure to soil with bat or bird droppings, often unrecognized

What are the key clinical findings for coccidioidomycosis, blastomycosis, and histoplasmosis?

• Coccidioidomycosis: Respiratory symptoms, fever, fatigue, eosinophilia

• Blastomycosis: Respiratory symptoms, skin and bone lesions

• Histoplasmosis: Respiratory symptoms, fever, arthralgia

What are common chest radiograph or CT findings in coccidioidomycosis, blastomycosis, and histoplasmosis?

• Coccidioidomycosis: Focal and diffuse infiltrates, cavities, pleural effusion, adenopathy, micronodular infiltrates

• Blastomycosis: Lobar consolidation, diffuse infiltrates, nodular infiltrates

• Histoplasmosis: Focal, diffuse, or cavitary infiltrates, with hilar or mediastinal lymphadenopathy

What is Paracoccidioidomycosis and where is it endemic?

Paracoccidioidomycosis, also known as South American blastomycosis, is a major dimorphic endemic fungal infection in Latin America.

What is the natural history and morphology of Paracoccidioides brasiliensis?

• At 25°C (saprobic phase): Hyaline, septate hyphae with intercalated chlamydoconidia

• At 37°C (parasitic phase): Yeast cells with single or multiple buds in a “pilot wheel” arrangement

How does infection with Paracoccidioides brasiliensis occur, and who is affected?

• Acquired by inhalation or traumatic inoculation

• Primary infection usually occurs in young people, often self-limited and flu-like

• Chronic pulmonary infection is more common in adult men, due to estrogen-mediated inhibition

• Reactivation years later can cause chronic progressive pulmonary disease and dissemination to oral and cutaneous sites

How is Paracoccidioidomycosis diagnosed?

• Yeast forms in clinical material (look for pilot wheel morphology)

• Differential diagnosis includes Cryptococcus neoformans and Blastomyces dermatitidis

• Culture confirms dimorphism

• Serologic testing can support diagnosis

How is Paracoccidioidomycosis treated?

• Itraconazole for ≥ 6 months in mild to moderate disease

• Amphotericin B for severe cases, followed by itraconazole or fluconazole

What is Talaromyces marneffei and where is it endemic?

Talaromyces (Penicillium) marneffei causes talaromycosis (penicillosis), primarily affecting HIV-infected individuals in Thailand and China. It is considered an early indicator of HIV infection in these regions.

What is the morphology of T. marneffei at different temperatures?

• 25°C (mold phase): Typical sporulating structures with red pigment production

• 37°C (tissue phase): Yeast-like cells that divide by fission, often intracellular in mononuclear phagocytes

What are the clinical features of talaromycosis?

• Begins with pulmonary symptoms

• Can disseminate and infect mononuclear phagocyte systems

• Skin lesions after hematogenous spread resemble molluscum contagiosum

• Differential diagnosis includes tuberculosis, leishmaniasis, and other AIDS-related infections like histoplasmosis and cryptococcosis

How is talaromycosis diagnosed?

• Direct examination of clinical specimens

• Mold phase shows Penicillium-like sporulation

• Red pigment production and confirmation of dimorphism help confirm identity

How is talaromycosis treated?

• Amphotericin B for severe disease

• Azoles (e.g., itraconazole) for maintenance or mild/moderate disease