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HMS Immunology and Microbiology > Fungi, Antifungals, and Endemic Mycoses > Flashcards

Fungi, Antifungals, and Endemic Mycoses Flashcards

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1
Q

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

A

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

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2
Q

Yeast

A

Unicellular fungi that divide by budding

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3
Q

Molds

A

Multicellular fungi with form hypae fillaments

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4
Q

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

A

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

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5
Q

Septate vs Aseptate hyphae

A
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6
Q

____ can form yeast and mold forms simultaneously.

A

Candida albicans can form yeast and mold forms simultaneously.

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7
Q

____ fungi may appear as yeast or mold.

A

dimorphic fungi may appear as yeast or mold.

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8
Q

3 Major mechanisms of antifungals

A
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9
Q

Flucytosine

A

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.

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10
Q

Adverse effects of flucytosine

A

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.

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11
Q

Ergosterol

A

Unique to fungal membranes, and required for fungus survival

Target of antifungals via two mechanisms: synthesis and membrane function

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12
Q

Mechanism of polyenes

A
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13
Q

Most perscribed polyene in clinical medicine

A

liposomal Amphotericin B

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14
Q

Adverse effects of Amphotericin B

A

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

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15
Q

Rigors

A

chills

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16
Q

Nystatin

A

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

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17
Q

Enzyme which produces ergosterol

A

14-α-demethylase

This enzyme is the target of azole antifungals.

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18
Q

Mechanism of action of azoles

A

Inhibition of 14-α-demethylase.

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

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19
Q

Commonly used azoles

A

Fluconazole

Voriconazole

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20
Q

Adverse effects of azoles

A

Nausea, vomitting, elevated transaminases

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

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21
Q

1,3-β-D-glucan

A

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.

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22
Q

Echinocandins

A

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.

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23
Q

Adverse effects of echinocandins

A

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

Phlebitis can occur during infusion.

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24
Q

Phlebitis

A

Inflammation of vein during phlebotomy

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25
Q

Endemic mycoses

A

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.

26
Q

Important endemic mycoses of the US

A
  • Histoplasmosis
  • Blastomycosis
  • Coccidiodomycosis
27
Q

Source of Histoplasma capsulatum infection

A

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.

28
Q

Histoplasma capsulatum

A

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.

29
Q

Geographic range of endemic mycoses

A
30
Q

Histoplasma capsulatum-mediated disease

A
  • 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
31
Q

Histoplasma capsulatum-mediated damage

A
  • 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
32
Q

Acute disseminated histoplasmosis

A

fever, chills, fatigue, mucous membrane ulcers, hepatosplenomegaly, and pancytopenia;

in some cases, adrenal insufficiency, sepsis syndrome, and disseminated intravascular coagulation occurs

33
Q

Pancytopenia

A

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

34
Q

Chronic progressive disseminated histoplasmosis

A

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.

35
Q

Diagnosing histoplasmosis

A
  • 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
36
Q

Treatment of histoplasmosis

A
  • 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
37
Q

Prevention of histoplasmosis

A

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.

38
Q

Source of Blastomyces dermatitidis infection

A

Blastomycosis is endemic to North America, as well as Central and East Africa.

The conidia of B. dermatitidis are inhaled into the lungs.

39
Q
A

Histoplasma in MΦ

40
Q

Blastomyces dermatitidis-mediated disease

A
  • 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
41
Q

Blastomyces dermatitidis-mediated damage

A
  • 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
42
Q
A

Blastomycosis skin lesions

43
Q

Diagnosing blastomycosis

A
  • 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
44
Q

Treatment of Blastomycosis

A
  • 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
45
Q

Prevention of blastomycosis

A

None currently established

46
Q
A

Blastomycosis on H and E

47
Q

Pathogenic Coccidioides

A

Coccidioides immitis and Coccidioides posadasii

48
Q

Source of Coccidioides infection

A

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

49
Q

Coccidioides-mediated disease

A
  • 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
50
Q

Coccidioides-mediated damage

A
  • 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
51
Q

Arthritis vs Arthraglia

A
52
Q

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

A

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

53
Q

Diagnosing coccidioidomycosis

A
  • Culture from effected tissues/fluids
  • Histopathological demonstration of spherules in tissues is also diagnostic
  • Assays for antibodies against Coccidioides
54
Q
A

Coccidioides spherule

55
Q

Treatment of coccidioidomycosis

A

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 itraconazole or fluconazole when stable
  • Coccidioidal meningitis can usually be treated successfully with fluconazole, but therapy must be lifelong
56
Q

Prevention of coccidiodomycosis

A

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

57
Q

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

A

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

58
Q

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

A

Wear an N95 respirator

59
Q

___ are pathopneumonic for coccidioides.

A

spherules are pathopneumonic for coccidioides.

60
Q

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

A

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.

HMS Immunology and Microbiology (27 decks)

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