Mycology II - Endemic

Question 1

Three Endemic Fungal Pathogens and Diseases

Answer 1

Histoplasma capsulatum (Histo) - Histoplasmosis
Blastomyces dermatitidis (Blasto) - Blastomycosis
Coccidiodes immits (Cocci) - Coccidioidmycosis

Question 2

Morphology of fungi

Answer 2

Fungi undergo “phenotype switching” and are dimorphic

Morphology is thermally regulated-

Question 3

Form of fungi

Answer 3

In environment all three fungi are free-living molds
In host: Histo, blasto become a budding yeast
In host: Cocci become endosporulating spherule

Question 4

Most often route of infection

Answer 4

Respiratory tract via small particles (2-5 micrometers)
Primary site of infection is lung
Can become localized and cause pneumonia or disseminate via the blood

Question 5

Alternate route of infection

Answer 5

Cutaneous lesions as primary sites

Lesions can also be result of dissemination

Question 6

Does a patient need to be immunocompromised to contract these fungi?

Answer 6

No, but usually infection is mild in immunocompetent patients.

Question 7

Are these fungi considered contagious?

Answer 7

No, normally not transmitted between people or animals.

Question 8

Method for definitive diagnosis

Answer 8

Microscopic examination of stains and histology plus any additional laboratory cultivation

Question 9

Differences in endemic areas

Answer 9

Blasto: Across the central and southeastern parts of the country (Mississippi + Ohio rivers + Great Lakes)
Histo: Triangle from Illinois, Louisiana, West Virginia (Mississippi + Ohio rivers)
Cocci: Southwest

Question 10

Differences between types

Answer 10

Most important: Antifungal drug therapy
Others: Morphology, clinical syndromes, anatomical targets of dissemination, danger to immunocompromised, virulence determinants, possibility of latency and reactivation

Question 11

Ecology of histo

Answer 11

Moist, rich, acidic soil
Bird and bat guano
Bats can be naturally infected, birds are not

Question 12

Geographic distribution of histo

Answer 12

Most common endemic mycosis in US and fungal respiratory infection in the world
Incidence of histoplasmin in some geographic regions exceeds 85%
Nearly all lifelong residents of fendemic areas are exposed by 20 yo

Question 13

Morphology of histo

Answer 13

In envrionment: Multinucleated branched hyphae with microconidia and macroconidia
In host: Oval budding yeast (2-4 micrometers) with narrow bud neck, found inside mononuclear phagocytes and extracellularly

Question 14

Primary infection of histo

Answer 14

Microconidia become airborne and penetrate alveoli
Then are engulfed by macrophages and convert to yeast form, beginning to replicate
Cellular immunity develops within 2 weeks, CD4+ T-cells are vitally important
By 3-6 weeks, become hypersensitive to histo Ag, yielding positive response to skin Ag test
Most frequent result of infection (75-90% of the time) in immunocomptent is asymptomatic or non-specific flu-like syndrome, 3-17 days after exposure

Question 15

Clinical symptoms of histo (in order of declining incidence)

Answer 15

Pulmonary - Resembles miliary TB on X-ray, lesions in lung
Acute pericardititis - 5% of symptomatic patients, result of immunologic response in the mediastinal lymph nodes
Dissemination: 1/2000 immunocompetent, 4-27% of immunocompromised, metastatic sites usually rich in mononuclear phagocytic cells
Occular histoplasmosis syndrome - Retinal scarring from host fibrosing inflammatory response
Fibrosing mediastinisis - Enlargement of multiple lymph nodes undergoing necrosis, causing Ag leakage into the mediastinum; abnormal inflammatory response leads to fibrosis

Question 16

Strain virulence of histo

Answer 16

Microconidia have receptors for CD2/CD18 integirns on macrophage surface initiating phagocytosis
Survices oxidative burst and can neutralize peroxide
Modulates phagolysomal pH to be less acidic

Question 17

Antifungal drug therapy of histo

Answer 17

Not all clinical manifestations require drug treatment

Anti-fungal drugs are considred a therapeutic adjunct to assist host immune response

Question 18

Can histo remain latent and then reactivate?

Answer 18

Probably yes, although incidence rates are unknown and is heavily based on anecdotal reports

Question 19

Important challenges histo presents

Answer 19

Hard to differential diagnosis (blastomycosis, pneumonia, TB, etc)
Skin test in endemic area only representative of exposure not active infection
Organisms can be seen in PAS and GMS-stained specimens but hard to directly detect otherwise

Question 20

Ecology of Blasto

Answer 20

Rich moist soil

Question 21

Blastomycosis in Wisconsin

Answer 21

100 cases per year
7-50 cases per outbreak
44% in 10 northern-most counties
20% in Milwaukee area
3 deaths per year

Question 22

Morphology of Blasto

Answer 22

Environment: Uninucleate hyphae producing microconidia
Host: Large budding yeast (8 to 30 micrometers) with broad bud neck

Question 23

Primary Infection of Blasto

Answer 23

Inhalation of microconidia which transform at body temperature to yeast
Incubation time is 4-6 weeks (useful for differentiating from histo)
Primary pulmonary infections unapparent in 50% of patients
Infections indistinguishable from other lobar or segmented pneumonias
Trauma can lead to deep cut. infections (“Chicago (Carpenter) Disease”)

Question 24

Canine blasto

Answer 24

Common and serves as an indicator of human disease risk in shared environment
No evidence of animal to human transmission

Question 25

Clinical Syndrome of Blasto

Answer 25

Blasto can be benign and self-limiting or a chronic granulomatous
Can be coincident with bronchogenic carcinoma, histo, TB, or other severe pulmonary disease
Unlike TB, blasto lesions rarely caseate or calcify
Cutaneous disease develops slowly as a subcut nodule or papule
Skin is the most common site of dissemination in about 20-40% of cases with dissemination
Other dissemination sites: bone (10-25%), UG tract (5-15%), CNS (5%)

Question 26

Strain Virulence of Blasto

Answer 26

Binds to integrins on host macrophages
Does not necessarily lead to phagocytosis due to blasto’s size
WI-1 mediates the binding
Contains BAD1 to prevent complement deposition on yeast cell

Question 27

Does blasto undergo latency and reactivation?

Answer 27

Rarely

Question 28

Challenges presented by Blasto

Answer 28

Differential diagnosis from pneumonia, TB, lung cancer

Differentiating primary from metastatic cut. lesions

Question 29

Ecology of cocci

Answer 29

Soil rich in organic material, hot/semi-arid climates
Highest incidence is in late summer or fall, when dusty conditions exist leading to soil disruption that disperse the arthroconidia

Question 30

Epidemiology of cocci

Answer 30

20,000 cases/yr

Infection is solely in endemic regions

Question 31

Morphology of cocci

Answer 31

Environment: Septate multicellular hyphae with alternate cells developing into barrel-shaped arthroconidia (“joint” seperated coindia)

Host: Arthroconidia convert within 72 hours into large spherules, which contin numerous endospores. Spherule ruptures releasing endospores to reproduce

Question 32

Primary infection of cocci

Answer 32

Infection via respiratory route
Can develop to a granulomatous respiratory infection
Caseation without calcification may occur

Question 33

Immune response to cocci

Answer 33

Humoral: IgM Ab to IgG Ab

Cell mediated response is ncessary for recovery

Question 34

Clinical syndromes of cocci

Answer 34

60% of primary pulmonary infections are asymptomatic, with only effect being hypersensitivity in skin test to coccidiodin
Symptoms range from mild flu-like syndrome developing 7-21 days after exposure to acute severe pneumonia
Dissemination occurs in approximately 1% of cases: Severe problems due to meninges, bone and skin being targets. Meningitis can lead to permanent neurological damage or death

Question 35

Special populations of cocci

Answer 35

Construction workers, Agricultural workers, Cattle ranchers
Racial bias towards “dark-skinned” populations
Special risk for pregnancy, highest risk during 3rd trimester, azole antifungal agents can be teratogenic
Special risk to AIDS patients being 3rd most life-threatening opportunisitic infection in patients, 25% of AIDS patients in endemic areas

Question 36

Strain virulence of cocci

Answer 36

Most virulent fungal pathogen

Question 37

Drug therapy of cocci

Answer 37

95% of acute episodes resolve without therapy

Question 38

Special challenges of cocci

Answer 38

Ethnic biases
Pregnancy
Awareness of disease outside of endemic areas, clinicians outside of endemic areas are relatively quick to biopsy

Question 39

Antifungal Drug Therapy Summary for Mild Pulmonary Endemic Fungi

Answer 39

Histo: None or itraconazole
Blasto: Itraconazole
Cocci: None

Question 40

Antifungal Drug Therapy Summary for Severe Disseminated Endemic Fungi

Answer 40

Amphotericin B for all