Fungi, Antifungals, and Endemic Mycoses

Question 1

___ fungal infections are common and treatable. ___ fungal infections usually only occur in immunocompromized inviduals and can be very deadly.

Answer 1

Superficial fungal infections are common and treatable. Invasive fungal infections usually only occur in immunocompromized inviduals and can be very deadly.

Question 2

Yeast

Answer 2

Unicellular fungi that divide by budding

Question 3

Molds

Answer 3

Multicellular fungi with form hypae fillaments

Question 4

___ may branch off of ___ and be caught up by wind, enabling spread of a mold.

Answer 4

Conidia (spores) may branch off of mycelium and be caught up by wind, enabling spread of a mold.

Question 5

Septate vs Aseptate hyphae

Answer 5

Question 6

____ can form yeast and mold forms simultaneously.

Answer 6

Candida albicans can form yeast and mold forms simultaneously.

Question 7

____ fungi may appear as yeast or mold.

Answer 7

dimorphic fungi may appear as yeast or mold.

Question 8

3 Major mechanisms of antifungals

Answer 8

Question 9

Flucytosine

Answer 9

5-fluorocytosine. The only pyrimidine antifungal.

Fungal cells deaminate 5-FC to 5-FU while mammalian cells do not. 5-FU goes on to replace uracil in RNA and inhibit translation. A separate downstream 5-FU metabolite also inhibits thymidylate synthase, preventing DNA replication.

Question 10

Adverse effects of flucytosine

Answer 10

In people with good renal function, nausea, diarrhea, vomitting observed.

More commonly with patients with poor renal function, suppression of bone marrow replication may occur, causing thrombocytopenia and neutropenia. May be due to accumulation of low levels of 5-FU in blood due to lack of filtration.

Question 11

Ergosterol

Answer 11

Unique to fungal membranes, and required for fungus survival

Target of antifungals via two mechanisms: synthesis and membrane function

Question 12

Mechanism of polyenes

Answer 12

Question 13

Most perscribed polyene in clinical medicine

Answer 13

liposomal Amphotericin B

Question 14

Adverse effects of Amphotericin B

Answer 14

Requires IV infusion and often leads to rigors, fever, hyper- or hypotension

Nephrotoxicity is very common, limits utility (reduces renal blood flow, toxic to tubular cells)

These side effects are reduced by liposomal preparation

Question 15

Rigors

Answer 15

chills

Question 16

Nystatin

Answer 16

Another polyene used clinically. Too toxic for systemic administration, only ever used topically.

Question 17

Enzyme which produces ergosterol

Answer 17

14-α-demethylase

This enzyme is the target of azole antifungals.

Question 18

Mechanism of action of azoles

Answer 18

Inhibition of 14-α-demethylase.

In addition to not producing ergosterol, toxic pre-metabolites build up and poison the cell.

Question 19

Commonly used azoles

Answer 19

Fluconazole

Voriconazole

Question 20

Adverse effects of azoles

Answer 20

Nausea, vomitting, elevated transaminases

Azoles also inhibit certain cytochrome p450 enzymes, which may increase toxicity from other drugs, namely warfarin and cyclosporine.

Question 21

1,3-β-D-glucan

Answer 21

Found in the cell wall of many fungi and required for cell wall integrity in fungi who possess it. Absent in mucor and Cryptococcus neoformans.

Used as an antigen to screen for and as a target for antifungals.

Question 22

Echinocandins

Answer 22

Antifungals which bind to and inhibit β(1,3) glucan synthase. Leads to depletion of 1,3-β-D-glucan in cell wall and eventual death of fungus.

Question 23

Adverse effects of echinocandins

Answer 23

Generally well tolerated. Sometimes cause fever, rash, nausea/vomiting.

Phlebitis can occur during infusion.

Question 24

Phlebitis

Answer 24

Inflammation of vein during phlebotomy

Question 25

Endemic mycoses

Answer 25

Caused by fungi that are **geographically restricted** to certain environmental areas. **All can infect healthy individuals** (not just the immunosuppressed). All the fungi that cause endemic mycoses are **dimorphic,** existing in the environment as molds and in hosts as either yeasts or spherules.

Question 26

Important endemic mycoses of the US

Answer 26

* Histoplasmosis * Blastomycosis * Coccidiodomycosis

Question 27

Source of *Histoplasma capsulatum* infection

Answer 27

**Endemic to US** as well as certain other areas worldwide. Within endemic areas, **as much as 90% of population infected**. **Infection occurs when the conidia** from the mold **are inhaled** into the lungs.

Question 28

*Histoplasma capsulatum*

Answer 28

**Soil fungus** whose growth is enhanced by the **high nitrogenous content of earth** that has been **fertilized** by bird or bat **guano**. Clusters of infection occur with **spelunking, demolition of old buildings, and construction work** that _disrupts soil._

Question 29

Geographic range of endemic mycoses

Answer 29

Question 30

*Histoplasma capsulatum*-mediated disease

Answer 30

* Aquired via **respiratory route** from disrupted soil * Extent of disease dependent on **fungal load** acquired and extent of **cellular immune response** * **Majority** have **no symptoms or minor respiratory symptoms** * **Small portion** have **fever, chills, anorexia, dry cough, pneumonitis, hylar/mediastinal lymphadenopathy,** sometimes even hypoxemia * Patients with **underlying COPD** at risk for **chronic cavitary pulmonary histoplasmosis**, a progressive infection that **mimicks reactivated tuberculosis** * Acute disseminated histoplasmosis or chronic progressive histoplasmosis

Question 31

*Histoplasma capsulatum*-mediated damage

Answer 31

* When organism enters lungs, it turns into yeast form. * Phagocytosed by MΦ or PMN and resist killing by raising phagosomal pH * Takes ~3 weeks for T cells to mature and enable MΦ killing of yeast (cellular immunity) * Dissemination occurs in virtually 100% of patients, just to different extents

Question 32

Acute disseminated histoplasmosis

Answer 32

**fever, chills, fatigue, mucous membrane ulcers, hepatosplenomegaly**, and **pancytopenia**; in some cases, **adrenal insufficiency**, **sepsis** syndrome, and **disseminated intravascular coagulation** occurs

Question 33

Pancytopenia

Answer 33

Combination of three symptoms: anemia, thrombocytopenia, neutropenia. Sometimes also lymphocytopenia/monoctyopenia

Question 34

Chronic progressive disseminated histoplasmosis

Answer 34

Seen in older adults who have **no obvious immune deficiency** but for some reason are **unable to contain *H. capsulatum*.** **If not treated, patients with the chronic disease die** from progressive infection of the **liver**, **spleen, bone marrow, adrenals**, and other organs.

Question 35

Diagnosing histoplasmosis

Answer 35

* **Sputum/blood/tissue/bodily fluid culture**, takes **~6 weeks** * **Histopathological demonstration** of the small **intracellular yeasts** in samples from infected tissues (particularly within macrophages and neutrophils) - **highly suggestive** * **Immunoassay** for **polysaccharide antigen from the cell wall** of H. capsulatum - **effective for acute primary pulmonary,** but **NOT effective for chronic or tissue-localized infections**

Question 36

Treatment of histoplasmosis

Answer 36

* **Itraconazole** for **mild-to-moderate pulmonary** or **disseminated** histoplasmosis * **Amphotericin B** initially for **severe/progressive infections**, **switch to itraconazole when stable** * You may notice, this is the same recommendation for blastomycosis

Question 37

Prevention of histoplasmosis

Answer 37

**Use of respirators** when tearing down **old barns and chicken coops** or other areas that have housed birds and bats is highly recommended. **Immunosuppressed persons should not take part in those activities.**

Question 38

Source of *Blastomyces dermatitidis* infection

Answer 38

Blastomycosis is endemic to **North America**, as well as **Central and East Africa.** The **conidia** of *B. dermatitidis* are **inhaled** into the lungs.

Question 39

Answer 39

*Histoplasma* in MΦ

Question 40

*Blastomyces dermatitidis*-mediated disease

Answer 40

* Spores are inhaled * Starts as pneumonia * **Extensive pulmonary load** may have **fever, chills, anorexia, fatigue, dry cough, and patchy pneumonitis** on chest radiograph * With **extensive exposure**, **even in healthy hosts,** bilateral diffuse **nodular infiltrates**, **hypoxemia**, and **acute respiratory distress syndrome** can occur * **Skin lesions** due to hematogenous dissemination: May be **single or multiple**, have **heaped-up borders** with **small central microabscesses**, or manifest as **ulcerated lesions** * **Recurrence** not uncommon

Question 41

*Blastomyces dermatitidis*-mediated damage

Answer 41

* **Inhaled spores** * **Multiply in lungs** and cause pneumonia * **Secondary migration through blood** and replication at sites in **skin** * **Cell-mediated immunity** is clearly important in eradication of infection, but **neutrophils / Th17** also be important * **Yeast cells can remain viable within granulomas for years** and may cause **recurrence**

Question 42

Answer 42

Blastomycosis skin lesions

Question 43

Diagnosing blastomycosis

Answer 43

* **Sputum/skin/tissue culture**, **~weeks** * **Histopathological demonstration** in tissues of large, **thick-walled yeasts with single broad-based buds** - **highly suggestive** * Test for **Blastomyces antigen** useful for **disseminated/extensive infection**

Question 44

Treatment of Blastomycosis

Answer 44

* **Itraconazole** for **mild-to-moderate pulmonary or cutaneous blastomycosis** * **Amphotericin B initially** for **severe infection**, then **switch to itraconazole when stable.** * You may notice, this is the same recommendation for histoplasmosis

Question 45

Prevention of blastomycosis

Answer 45

None currently established

Question 46

Answer 46

Blastomycosis on H and E

Question 47

Pathogenic *Coccidioides*

Answer 47

*Coccidioides immitis* and *Coccidioides posadasii*

Question 48

Source of *Coccidioides* infection

Answer 48

Coccidioides species exist primarily in a distinctive ecosystem termed the **lower Sonoran life zone**, which includes **Arizona, southern California, the arid interior valleys in California, parts of New Mexico and Texas,** and areas in **Central and South America.** **Semiarid environment fosters the growth**. When conditions of rainfall, heat, and wind are correct, extensive “**blooms**” of the organism occur. In highly **endemic areas**, **as much as 80% of the population** has evidence of prior infection

Question 49

*Coccidioides*-mediated disease

Answer 49

* Highly infections spores contracted by inhalation * Mostly mild or sub-clinical lung symptoms * **Symptomatic acute pulmonary infection** occurs a **few weeks after exposure**: **fever, anorexia, fatigue, dry cough, and chest pain** * **Arthralgias and skin nodules** may develop: "**desert rheumatism**" or "valley fever" * Mostly benign, but progresses in some patients and may require antifungals * Disseminated coccidioidomycosis occurs more in people of African or Filipino ancestry, pregnant women, and those with cell-mediated immunodeficiencies: any organ may be involved, chronic meningitis may occur and may be fatal * May be recurrent

Question 50

*Coccidioides*-mediated damage

Answer 50

* **Inhaled into lung**, where **arthroconidia transform** into distinctive **large spherules** that **fill with endospores** * **Spherules resist phagocytosis** * **May disseminate** in some patients * Control requires **cell-mediated immunity** * **Reactivation** of an old focus of infection is possible **years later**

Question 51

Arthritis vs Arthraglia

Answer 51

Question 52

Patients with managed chronic coccidioides-mediated meningitis may ___ if \_\_\_.

Answer 52

Patients with chronic coccidioides-mediated meningitis may **relapse** if **therapy is stopped**.

Question 53

Diagnosing coccidioidomycosis

Answer 53

* **Culture** from effected tissues/fluids * **Histopathological demonstration** of **spherules** in tissues is also diagnostic * **Assays for antibodies against Coccidioides**

Question 54

Answer 54

Coccidioides spherule

Question 55

Treatment of coccidioidomycosis

Answer 55

Of all endemic mycoses, this is the **most difficult to treat**. Relapsing is very frequent. * **Itraconazole of fluconazole** for **mild-to-moderate coccidioidomycosis** * **Amphotericin B initially** for patients with **severe infection,** switch to it**raconazole or fluconazole when stable** * **Coccidioidal meningitis** can usually be treated successfully with **fluconazole**, but **_therapy must be lifelong_**

Question 56

Prevention of coccidiodomycosis

Answer 56

**Prevention is difficult** in the endemic area because the organism is **so readily dispersed**

Question 57

Why are endemic mycoses not transmissible person-to-person?

Answer 57

They only produce spores in mold-form, but only exist as yeast-form within people

Question 58

How should you prevent spore inhalation in at-risk individuals?

Answer 58

Wear an N95 respirator

Question 59

\_\_\_ are pathopneumonic for coccidioides.

Answer 59

**spherules** are pathopneumonic for coccidioides.

Question 60

\_\_\_\_ may be used to diagnosis histoplasmosis as well as to track progress of therapy.

Answer 60

**Urine testing** may be used to diagnosis histoplasmosis as well as to track progress of therapy. Note that it is more sensitive for disseminated than lung-localized disease.