Fungal infections 1 Flashcards
most neglected CNS infections
fungal
Hardest to treat – highest mortality and morbidity
Fungal diversity
one of the most diverse phylogenetic groups
Many are common environmental organisms
They inhabit all ecosytems (soil, water, air)
Phylogenetics
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).
Why are fungal infections the hardest to treat
Dimorphic fungi
fungi that have a yeast (or yeast-like) phase and a mold (filamentous) phase
species of fungi
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
primary vs opportunistic fungi
primary - infect anyone
opportunistic - infect immunocompromised individuals
Classification of mycoses is based on
site or virulence
site classification of mycoses
- Superficial – skin, hair, nails [athletes foot]
- Subcutaneous – lower levels of the skin; fat; mucous membranes [vaginal yest infection]
- Systemic or invasive – internal organs [cryptococl meningitis]
Requirements for fungi to cause systemic disease in humans
- High temperature tolerance (most die at 37 °C) [most environmental are at room temp]
- Ability to invade (crossing of physical barriers, skin/saliva inate barriers)
- Ability to obtain nutrients and grow [ex. lungs - very little food]
- Resistance to the immune system
virulence classification of mycoses
- Primary – can infect healthy, immunocompetent individuals.
are uncommon, limited niches, usually treatable if diagnosed correctly and timely - 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.)
Diagnosis of mycoses
Most common endemic mycosis in Americas
Histoplasmosis (Histoplasma)
In the US, around the Ohio and Mississippi river valleys
- moderate temperature and soil rich in guano
Histoplasmosis (Histoplasma) dimorphic nature
Thermally dimorphic (temperature is signal)
hypha in nature (multicellular) → yeast inside host
Histoplasma capsulatum is a ___ pathogen
primary
Inhaled microconidia → lung infection
Histoplasma capsulatum virulence mechanisms
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]
Histoplasma to CNS
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)
Histoplasma clinical manifestations
Histoplasmosis diagnosis
Histoplasmosis treatment
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
Histoplasmosis at risk individuals
- HIV/AIDS
- Medical immunosuppression
- COPD
- Smoking
- Living in endemic area
Valley fever
Coccidioides
two species - C. immitis (most common) and C. posadasii
Are primary pathogens
Also a dimorphic, hypha → spherule
Valley fever region
Abundant in the soil in the southwestern US, and parts of Mexico and Central and South America
Valley fever infection by
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!
Valley fever exposure / at risk groups
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
Valley fever clinical presentation
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
Valley fever CSF analysis
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%
Valley fever MRI
may reveal predominantly meningeal enhancement of the base of skull
Necessary to rule out hydrocephalus or ischemic complications
Valley fever diagnosis
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]
Valley fever treatment
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%
Climate change increasing spread of endemic fungal infections
Most common fungal CNS infection
Cryptococcus – C. neoformans and C. gattii
environmental yeast found worldwide
C. neoformans vs S. cerevisiae
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
Cryptococcus – C. neoformans and C. gattii virulence factors
- Capsule [grow in body]
- Thermotolerance [grow even at 41, 42 C - birds]
- Melanin [protects from oxidatve stress, survives inside macrophage]
- Urease, phospholipase, and multiple secreted proteases [proteases - degrade BBB]
C. neoformans infection route
True neurotropic - but it is acquired by inhalation
Extrapulmonary dissemination a prerequisite
C. neoformans survival in body
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
Cryptococcus CNS invasion
Mix of routes for Cryptococcus CNS invasion promote each other
Free fungi activates BMECs
Activated BMECs recruits phagocytes
Recruited phagocytes weakens BBB, more free fungi crossing
Cryptococcus pathogenesis immune response
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)
Cryptococcosis clinical manifestations
Cryptococcosis at-risk groups
Cryptococcosis complications
Cryptococcosis diagnosis
Cryptococcosis treatment
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
