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A - Neuroinfectious Diseases 2 > Fungal infections 1 > Flashcards

Fungal infections 1 Flashcards

1
Q

most neglected CNS infections

A

fungal

Hardest to treat – highest mortality and morbidity

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2
Q

Fungal diversity

A

one of the most diverse phylogenetic groups

Many are common environmental organisms

They inhabit all ecosytems (soil, water, air)

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3
Q

Phylogenetics

A

systematic study of reconstructing the past evolutionary history of extant species or taxa, based on present-day data, such as morphologies or molecular information (sequence data).

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4
Q

Why are fungal infections the hardest to treat

A
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5
Q

Dimorphic fungi

A

fungi that have a yeast (or yeast-like) phase and a mold (filamentous) phase

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6
Q

species of fungi

A

Estimated to be ~3 million species – only ~120,000 have been described

~40 are frequent human pathogens
Far fewer invade the CNS

Always posed threat to public health but increasing recently

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7
Q

primary vs opportunistic fungi

A

primary - infect anyone

opportunistic - infect immunocompromised individuals

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8
Q

Classification of mycoses is based on

A

site or virulence

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9
Q

site classification of mycoses

A
  1. Superficial – skin, hair, nails [athletes foot]
  2. Subcutaneous – lower levels of the skin; fat; mucous membranes [vaginal yest infection]
  3. Systemic or invasive – internal organs [cryptococl meningitis]
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10
Q

Requirements for fungi to cause systemic disease in humans

A
  1. High temperature tolerance (most die at 37 °C) [most environmental are at room temp]
  2. Ability to invade (crossing of physical barriers, skin/saliva inate barriers)
  3. Ability to obtain nutrients and grow [ex. lungs - very little food]
  4. Resistance to the immune system
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11
Q

virulence classification of mycoses

A
  1. Primary – can infect healthy, immunocompetent individuals.
    are uncommon, limited niches, usually treatable if diagnosed correctly and timely
  2. Opportunistic – only infect the immunocompromised
    are more frequent, ubiquitous, usually fatal
    • Successes in medicine have increased the number of people at risk (organ transplants, steroids, etc.)
    • Importance of vaccines - currently are none but everyone becomes immunocompromised at some point (age, pregnancy.)
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12
Q

Diagnosis of mycoses

A
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13
Q

Most common endemic mycosis in Americas

A

Histoplasmosis (Histoplasma)

In the US, around the Ohio and Mississippi river valleys
- moderate temperature and soil rich in guano

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14
Q

Histoplasmosis (Histoplasma) dimorphic nature

A

Thermally dimorphic (temperature is signal)

hypha in nature (multicellular) → yeast inside host

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15
Q

Histoplasma capsulatum is a ___ pathogen

A

primary

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16
Q

Inhaled microconidia → lung infection

A
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17
Q

Histoplasma capsulatum virulence mechanisms

A

Mask their cell surface [so not recognized]

Survive inside macrophages (but dendritic cells kill them!) [transporters for nutrients]

Can induce macrophage adhesion and phagocytosis to hide there!

Secrete host of enzymes to survive [disrupt tight junctions - desciminate]

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18
Q

Histoplasma to CNS

A

Not neurotropic (usally restricted to lungs) - extrapulmonary dissemination may include CNS

Mostly in children

CNS invasion unclear, thought to be Trojan horse (can survive inside immune cells)

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19
Q

Histoplasma clinical manifestations

A
20
Q

Histoplasmosis diagnosis

A
21
Q

Histoplasmosis treatment

A

4 – 6 weeks of amphotericin B (first antifungal devoloped) followed by a year of itraconazole

Histoplasma antigen levels should be cleared, and CSF analysis should come back normal and brain lesions no longer present

In some patients, lifelong azole therapy is necessary to avoid relapse

22
Q

Histoplasmosis at risk individuals

A
  1. HIV/AIDS
  2. Medical immunosuppression
  3. COPD
  4. Smoking
  5. Living in endemic area
23
Q

Valley fever

A

Coccidioides

two species - C. immitis (most common) and C. posadasii

Are primary pathogens

Also a dimorphic, hypha → spherule

24
Q

Valley fever region

A

Abundant in the soil in the southwestern US, and parts of Mexico and Central and South America

25
Q

Valley fever infection by

A

breathing in the microscopic fungal spores

Conidia is easily aerosolized

Morphological change in host (temp)

Spherule fills with endospores and ruptures - Endospores seed other tissues, and develop more spherules

Innate response is key! - Mature spherules are too large!

26
Q

Valley fever exposure / at risk groups

A

dust from endemic areas

Prolonged soil exposure in endemic areas is a risk factor in healthy people → certain professions at-risk (eg. archaeologists)

Inhalation of spore → pulmonary infection

~10% of new infections will disseminate
CNS involvement mostly in immunosuppressed

high risk
AIDS, diabetes, chronic steroid therapy, and other immunosuppressive states

27
Q

Valley fever clinical presentation

A

Typical CNS presentation: chronic basilar meningitis [inflammation at bace of the skull)

Low-grade fever, chronic daily headache, and memory and attention problems → hydrocephalus and ischemic vasculitis

28
Q

Valley fever CSF analysis

A

reveal an eosinophilic pleocytosis, elevated protein (lisis of host cells) and low glucose (fungus is using the glucose)

culture is positive in only about 15%

29
Q

Valley fever MRI

A

may reveal predominantly meningeal enhancement of the base of skull

Necessary to rule out hydrocephalus or ischemic complications

30
Q

Valley fever diagnosis

A

Careful travel and exposure history is key! Delayed prognosis contributor to higher mortality

Gold standard - culture, but not always possible [also takes time - visualization on tissue enough for diagnosis]

31
Q

Valley fever treatment

A

Fluconazole initially; combinatorial with amphotericin B in severe cases

When hydrocephalus present, shunt placement may be needed

Lifelong suppressive therapy may be needed

Mortality, despite treatment ~40%

32
Q

Climate change increasing spread of endemic fungal infections

A
33
Q

Most common fungal CNS infection

A

Cryptococcus – C. neoformans and C. gattii

environmental yeast found worldwide

34
Q

C. neoformans vs S. cerevisiae

A

neoformans

fibers - one of main virulence factors, once in body capsul can grow larger then cell

opurtunitsitc - found everywhere

cerevisiae (Brewer’s yeast)

endemic - primary

35
Q

Cryptococcus – C. neoformans and C. gattii virulence factors

A
  1. Capsule [grow in body]
  2. Thermotolerance [grow even at 41, 42 C - birds]
  3. Melanin [protects from oxidatve stress, survives inside macrophage]
  4. Urease, phospholipase, and multiple secreted proteases [proteases - degrade BBB]
36
Q

C. neoformans infection route

A

True neurotropic - but it is acquired by inhalation

Extrapulmonary dissemination a prerequisite

37
Q

C. neoformans survival in body

A

They are antiphagocytic - capsule - enlarges and sheds

shedding - can form granuloma and/or titan cell. Titan cell - cannot be eaten by macrophages - associated with latency

Movment:

They also can survive inside macrophages

They can escape host cells without lysis (or with)

They can undergo cell-to- cell direct transfer

They can use phagocytes as Trojan horses

38
Q

Cryptococcus CNS invasion

A
39
Q

Mix of routes for Cryptococcus CNS invasion promote each other

A

Free fungi activates BMECs

Activated BMECs recruits phagocytes

Recruited phagocytes weakens BBB, more free fungi crossing

40
Q

Cryptococcus pathogenesis immune response

A

Interactions with innate are key

3 main immune responses: Th1,
Th2, and Th17
- Th1 → protective→ pro inflammation
- Th2 → permissive → anti inflammation [Capsule induces Th2 in absence of normal response - wants to be permissive in environment]

BALANCE
too much T1 → collateral damage

Absence of T-cell response AIDS - permissive (hence susceptibility in immunosuppression)

41
Q

Cryptococcosis clinical manifestations

A
42
Q

Cryptococcosis at-risk groups

A
43
Q

Cryptococcosis complications

A
44
Q

Cryptococcosis diagnosis

A
45
Q

Cryptococcosis treatment

A

Treat ICP – associated with poor neurological outcomes
- Successive LPs, or shunt

Antifungal treatment ASAP:
AmpB/flucytosine - toxic but effective, expensive
Fluconazole - cheap, suboptimal, toxic, long-term

In AIDS avoids IRIS  delay start/restarting of HART
- If emergency, start HART with steroids
- Complication by co-infections

A - Neuroinfectious Diseases 2 (9 decks)

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