Id 3F1: Opportunistic Mycoses

Front 1

Basic mycology terms

Yeast
Mold
Dematiaceous
Dimorphic

Back 1

• Yeast - a fungi from the family Saccharomycetaceae, including S. cerevisiae (baker's yeast). The term “yeast like” generally used for fungi that is round and reproduces by budding

• Mold - filamentous/ hyphal fungus. A colony on agar generally appears fuzzy, rather than smooth. Reproduce by spores

• Dematiaceous - dark-colored (green, brown, or black) fungi whose hyphae are pigmented

• Dimorphic - capable of producing both hyphae and yeast, depending on environment

Front 2

Common & emerging fungal pathogens

• Opportunistic yeasts

Back 2

– Candida spp
– Trichosporon beigelii
– Cryptococcus neoformans

Front 3

Common & emerging fungal pathogens

• Dematiaceous molds

Back 3

– Alternaria spp
– Pseudallescheria boydii
– Cladosporium spp
– Scedosporium prolificans
– Wangiella spp

Front 4

Common & emerging fungal pathogens

• Endemic dimorphic fungi

Back 4

– Histoplasma capsulatum
– Coccidioides immitis
– Blastomyces dermatitidis
– Penicillium marneffei
– Sporothrix schenckii

Front 5

Common & emerging fungal pathogens

• Hyaline molds

Back 5

– Aspergillus spp
– Zygomycetes
– Fusarium spp

Front 6

Common & emerging fungal pathogens
• Other fungi -

Back 6

Pneumocystis jiroveci

Front 7

What stain is taken up by fungi cell wall?

Back 7

Silver stain

Front 8

Which is only encapsulated yeast we will be talking about?

Back 8

Cryptococcus neoformans

Front 9

Cryptococcus neoformans

Encapsulated?
Where found?
Route of inoculation?

Back 9

• Encapsulated yeast
• Widely distributed in the environment
– Found in bird guano (esp. pigeons, turkeys, & chickens) and soil

• Route of inoculation - inhalation

Front 10

Cryptococcosis
Risk factors

What accounts for majority of cases?

Other risk factors?

Back 10

• HIV infection (accounts for majority of cases)

Others:
• Systemic lupus erythematosus
• Lymphoproliferative disorders (e.g., CLL)
• Cirrhosis
• Sarcoidosis
• Organ transplantation
• Corticosteroid therapy
• Peritoneal dialysis
• HIV-negative CD4+ T-cell lymphopenia
• Hyper-IgM syndrome
• Hyper-IgE syndrome
• Monoclonal antibodies therapy (e.g., infliximab)

Front 11

Cryptococcosis
Clinical Presentation

Main presentations to think about? (3)

• Central Nervous
System

• Pulmonary disease

• Disseminated disease

• Skin

• GI

Back 11

Meningitis, Pulmonary Nodules, Cryptococcemia - main ones to think about

• Central Nervous
System
– Meningitis (esp. HIV+ pts)
– Cryptococcoma (brain or
spinal abscess)

• Pulmonary disease
– Pulmonary nodules (esp. non-
HIV pts)
– Lobar pneumonia
– Cavitary lesions
– Hilar adenopathy
– Miliary pattern

• Disseminated disease
– Cryptococcemia
• Skin
– Papules (molluscum-like)
– Subcutaneous abscesses
– Cellulitis

• Gastrointestinal
– Peritonitis
– Crohn’s-like ulcers
– Hepatitis

Front 12

Cryptococcosis & HIV / AIDS

Seen mostly in pts w/ CD4+ count <?

• Majority of AIDS pts w/ cryptococcosis develop _______or ___________

• AIDS pts w/ cryptococcal infection require _______________ (duration of therapy) w/ oral _________ (drug), unless:
– _______ & ____________

Back 12

• Prior to effective combination antiretroviral therapy - 5-8% of HIV+ pts developed cryptococcosis

• Seen mostly in pts w/ CD4+ count <50 cells/μL (AIDS-defining illness)

• Majority of AIDS pts w/ cryptococcosis develop meningitis or meningoencephalitis
– Only ~ 25-33% of pts have classic meningeal symptoms & signs
(e.g., neck stiffness or photophobia)

– 75% have CSF opening pressure (>200 mm H20)
– 75% have positive blood cultures for cryptococcus

• AIDS pts w/ cryptococcal infection require life-long suppression w/ oral fluconazole, unless:
– Asymptomatic & CD4 count increases & stays >100-200 w/
antiretroviral therapy

Front 13

Cryptococcal meningitis

• Typically presents as a ______ ________ / ___________

– Symptoms?

• CSF findings:?

• Diagnosis:
– _________ antigen (sensitivity 90-95%)

– ______ ink - encapsulated yeast (sensitivity - 80% HIV; 50% non-HIV)

– _______: growth of encapsulated yeast

Back 13

• Typically presents as a subacute meningitis / meningoencephalitis
– Headache, fever, malaise, + neuropsychiatric symptoms

• CSF findings: lymphocytosis, elevated protein, may have elevated opening pressure

• Diagnosis:
– Cryptococcal antigen (sensitivity 90-95%)

– India ink - encapsulated yeast (sensitivity - 80% HIV; 50% non-HIV)

– Fungal culture: growth of encapsulated yeast

Front 14

AIDS and Cryptococcus

– ___% have CSF opening pressure (>200 mm H20)

Back 14

75% have CSF opening pressure (>200 mm H20)

Knowing what the opening pressure is has prognostic value; so always do this if suspect cryptococcal infection

Front 15

Cryptococcal meningitis

• Indicator of poor prognosis?

• Long-term sequelae related to ↑ICP?

Back 15

• Indicator of poor prognosis
– Altered mental status (KEY!)
– Elevated CSF opening pressure (>400 mm H2O)
– Cryptococcal Ag titer >1:1024
– Poor CSF inflammatory response (<20 cells/uL)
– Multiple site of infection (blood, lung, etc)
– Underlying disease (malignancy)

• Long-term sequelae related to ↑ICP
– Communicating hydrocephalus (reduced uptake of CSF in arachnoid granulation tissue), blindness (optic nerve infarction due to really high pressures), deafness, cranial nerve palsy

Front 16

Cryptococcal meningitis -Treatment

• Antifungal therapy?

• Control of intracranial pressure (ICP) (>200 mmH2O)?

Back 16

• Antifungal therapy
– Amphotericin B +/- flucytosine x 2 weeks, followed by
– Fluconazole x 8 weeks (or until CSF cultures are neg.)
– Fluconazole long-term suppressive Rx in AIDS patients

• Control of intracranial pressure (ICP) (>200 mmH2O)
– Daily lumbar punctures for high ICP
– Lumbar drain for very high/ uncontrollable ICP
– May need ventriculoperitoneal shunt if uncontrollable

Front 17

Cryptococcosis (non-CNS)
Diagnosis

Biopsy?
Path: what kind of budding?
what stain used for capsule?

• Serum ________ ___ has
lower sensitivity compared to
CNS disease

Back 17

• Tissue biopsy for fungal culture, pathology

• Path: encapsulated narrowbased
budding, irregular yeast (5-10 μm dia.)
– capsule seen on special stains (mucocarmine stain)

• Serum cryptococcal Ag has
lower sensitivity compared to
CNS disease

Front 18

Cryptococcosis (non-CNS) -Treatment

• _________ to rule out CNS infection

• Serum _______ ____ (high titer - ↑burden)

• Antifungal therapy - duration depends on _________ and _______ of disease

– Pulmonary infection and immunocompetent host
• _______ 3-6 mo (asymptomatic) or 6-12 mos (symptomatic) __________

– Extra-pulmonary infection and/or compromised host
• Treat how?

Back 18

• Lumbar puncture to rule out CNS infection

• Serum cryptococcal Ag (high titer - ↑burden)

• Antifungal therapy - duration depends on underlying host and location of disease

– Pulmonary infection and immunocompetent host
• Fluconazole 3-6 mo (asymptomatic) or 6-12 mos
(symptomatic) fluconazole

– Extra-pulmonary infection and/or compromised host
• Treat the same as meningitis

Front 19

Pneumocystis jiroveci

Cellular?

Unable to grow readily where?


Human disease originally thought to be caused by ?

• Route of inoculation?

Back 19

• Unicellular fungi

• Unable to grow readily in vitro

• Human disease originally thought to be caused by P. carinii (thus PCP)

• Environmental niche unclear (colonizing hosts? Person-to person transmission?)

• Route of inoculation = inhalation

Front 20

Pneumocystis jiroveci

Infection occurs in ?
(impaired ________ immunity)
– HIV !!!! (CD4 count <_____)
– __________ (type of drugs)
– __________ (type of drugs)
– ______&_______ infants
– Blood?
– Collagen vascular disorders

Back 20

Infection occurs in immunocompromised hosts
(impaired cellular immunity)
– HIV !!!! (CD4 count <200)
– Corticosteroids
– Immunosuppressive drugs
– Premature & malnourished infants
– Hematologic malignancies
– Collagen vascular disorders

Front 21

Pneumocystis jiroveci pneumonia
Treatment?

Standard?

Alternatives?

For severe illness?

Back 21

• Trimethoprim/sufamethoxazole (TMP/SMX) = standard
• PO or IV x 21 days

• Alternatives: clindamycin + primaquine; atovaquone; dapsone; IV pentamidine

• Prednisone (for severe disease)
• 40 mg PO BID, days 1-5; then taper over 21 days.
• Severe disease = hypoxia (room air PaO2 <70 mmHg or A-a gradient >35 mmHg)

Front 22

Pneumocystis jiroveci pneumonia
Prognosis

• Overall mortality ~__%

• Poor prognostic indictors
– _____________
– _____________

• Complication - ___________

If someone presents with spontaneous __________ - think p. jiroveci

Back 22

• Overall mortality ~18%

• Poor prognostic indictors
– Non-HIV patient
– Respiratory failure - mechanical ventilation

• Complication - pneumothorax

if someone presents with spontaneous pneumothorax - think p. jiroveci

Front 23

Aspergillosis Ecology

Where found in environment?

• Isolated from? (4)

• A. _______ most common human
pathogen?

• Hospital outbreaks well recognized
– Associated with ______, __________(inappropriate control of dust exposure)

Back 23

Aspergillosis Ecology

• Ubiquitous in the environment

• Isolated from soil, air, human habitats, decaying matter

• A. fumigatus most common human
pathogen

• Found in 0.5-10% of normal sputa

• Hospital outbreaks well recognized
– Associated with ventilation systems, demolition (inappropriate control of dust exposure)

Front 24

Invasive aspergillosis

• Opportunistic pathogen, almost always in __________ patients
- What is primary risk factor?
- Others?

• Tendency for ______ invasion (leads to infarction and ________ _________)

Back 24

• Opportunistic pathogen, almost always in compromised patients
– Neutropenia = primary risk factor
– Bone marrow transplant
– Solid organ transplants
– Corticosteroid therapy
– Chronic granulomatous disease
– AIDS

• Tendency for vascular invasion (leads to infarction & tissue necrosis)

Front 25

Invasive pulmonary aspergillosis
Clinical features

• What kind of fever?

• __________
– occasionally severe & catastrophic

• New pulmonary ________

• Chest signs?

Back 25

• Fever, often low grade

• Hemoptysis
– occasionally severe & catastrophic

• New pulmonary infiltrates

• Chest pain
– may be pleuritic pain (pulmonary infarction)

• Cough

Front 26

Invasive pulmonary aspergillosis
Diagnosis

• CXR or CT scan showing ?

• Culture of organism from _________ or _________
– in _________ patient, sputum or nasal culture is very specific

• Serum ________ ___ assay
– Sensitivity > 90% profoundly immunocompromised patients, less in others

• _________ (best way to make diagnosis)

Back 26

• CXR or CT scan showing cavitation or “halo sign”

• Culture of organism from bronchial specimens or lung biopsy
– in neutropenic patient, sputum or nasal culture is very specific

• Serum galactomannan Ag assay
– Sensitivity > 90% profoundly immunocompromised patients, less in others

• Histopathology (best way to make diagnosis)

Front 27

Invasive pulmonary aspergillosis

Will show what on histo?

CT will show?

Back 27

Acute angle branching / septated hyphae

-“Halo sign”

Front 28

Non-pulmonary invasive Aspergillosis

• Sinusitis
affects which patients?
symptoms?
direct invasion where?
diagnosis by?

• CNS disease
– Characterize by?
– May occur in conjunction with?

• Skin
– 2 presentations:

Back 28

• Sinusitis
– Immunocompromised hosts
– Fever, cough, epistaxis, sinus discharge, HA
– Direct invasion into orbit, brain, palate
– Diagnosis: biopsy w/ fungal invasion

• CNS disease
– Mass lesion w/ cerebral edema
– May occur in conjunction w/ pulmonary disease

• Skin
– Disseminated disease (multiple lesions, rapidly ulcerative, necrotic)
– Local disease (burns, surgical wounds, catheter sites)

Front 29

Invasive Aspergillosis - Prognosis
• Overall Survival ~__%

• Poor prognostic indicators
– (3)

Back 29

• Overall Survival 58%

• Poor prognostic indicators
– Severe immunosuppression (allogenic BMT)
– Disseminated or extensive disease
– CNS disease (<10% overall survival)

Front 30

Invasive Aspergillosis -Treatment

• Reduce __________ (if possible)

• Duration of drug therapy based on what? is it long or short?
– _________ (drug of choice)
– ___________ (lipid formulation)
– ________+________ (no data)
– __________ (salvage)
– Itraconazole

Back 30

• Reduce immunosuppression (if possible)

• Duration of drug therapy based on clinical response (long)
– Voriconazole (drug of choice)
– Amphotericn B (lipid formulation)
– Voriconazole + caspofungin (no data)
– Caspofungin (salvage)
– Itraconazole

Front 31

Mucormycosis (Zygomycosis)

• Basically _____ mold

• Distribution?

• Sites of infection (in order of frequency)? (6)

Back 31

• Basically bread mold

• Infection due to a member of the Mucorales Order of Phyla Zygomyceta (Rhizopus spp., Mucor spp.)

• Widely distributed in the environment

• Sites of infection (in order of frequency)
– Rhinocerebral
– Pulmonary
– Cutaneous
– Gastrointestinal
– Central nervous system
– Other (renal)

Front 32

Mucormycosis Risk factors

One to remember for the boards?!?

(7)

Back 32

• Diabetic ketoacidosis (BOARDS!! EXAM!!)

• Neutropenia (also important)
• Hematological malignancies
• Iron chelating therapy (deferroxamine) given to reduce iron load in the body
• Protein-calorie malnutrition (esp.
gastrointestinal)
• Burns
• Trauma

Front 33

Mucormycosis Pathogenesis

• Inoculation
– ________ - deposit in nasal turbinate (rhinocerebral) or alveoli (pulmonary)

– Direct contact with ____ _______(cutaneous)

• Spreads through direct invasion (
hematogenous spread?)

• Tendency for vascular invasion
– _______ & ____________

Back 33

• Inoculation
– Inhaled - deposit in nasal turbinate (rhinocerebral) or alveoli (pulmonary)
– Direct contact with abraded skin (cutaneous)

• Spreads through direct invasion (no
hematogenous spread)

• Tendency for vascular invasion
– Thrombosis & tissue necrosis

Front 34

Rhinocerebral Mucormycosis

Symptoms (3)

• Signs
– Eye?
– Mouth?
– Nose?
– Brain?

Back 34

Symptoms
– Facial pain
– Headache
– Fever

• Signs
– Orbital cellulitis
– Invasion of the palate (erythema → ulcer → necrosis)
– Black nasal discharge (watch for this one!)
– Proptosis
– Cranial nerve deficits (esp. III, V and VII) --> the ones that travel skull base

Front 35

Mucormycosis - Other sites

Pulmonary?

Cutaneous?

GI?

Back 35

• Pulmonary
– Fever, dyspnea, cough (hemoptysis w/ necrosis)
– CXR = infiltrate or cavity

• Cutaneous
– Direct trauma, burns, contaminated dressings
– Can extend into deep tissue

• Gastrointestinal
– Extreme malnutrition
– Abdominal pain, distention, N/V,
Fever, abscesses

Front 36

Mucormycosis Diagnosis

Tissue diagnosis
– findings?

– vascular invasion
• findings?

Back 36

Tissue diagnosis
– Broad, non-septate hyphae w/ branching at right angles

– vascular invasion
• Culture - may be negative

Front 37

Mucormycosis Treatment & Prognosis

Primary therapy?

• Correction of the underlying risk factor(s)?

• Antifungal therapy (2)

• __ % overall mortality (like aspergillus)

• Poor prognosis if:
(2)

Back 37

Primary therapy: extensive surgical debridement

Correct diabetic ketoacidosis

• Antifungal therapy
– High-dose IV amphotericin B
– Posaconazole PO

• 50% overall mortality

• Poor prognosis
– Pulmonary disease, extensive involvement

Front 38

Sporotrichosis

• _______ fungi

• Environment Distribution?
– Associated with? (board question)

• Most cases follow ?

Back 38

• Dimorphic fungi

• Widely distributed in the environment
– Associated with soil, straw,
sphagnum moss, wood, rose
plants (board question)

• Most cases follow scratch or
other trauma – May be unrecognized

Front 39

Sporotrichosis Presentation

• Cutaneous lesion at site of trauma
– ___________
– ___________
– May develop additional lesions in _________ distribution

• Less common – (2)

• Immunocompromised hosts: same as above
– However, may ?

Back 39

• Cutaneous lesion at site of trauma
– Subcutaneous nodules w/ ulceration
– Scaly plaques
– May develop additional lesions in lymphatic distribution

• Less common – chronic septic arthritis, chronic cavitary pneumonia

• Immunocompromised hosts: same as above
– However, may disseminate hematogenously

Front 40

Sporotrichosis Diagnosis & Treatment

• Diagnosis?

• Treatment
– _________ 100-200 mg/day x 3-6 mos
– (2)?

• Prognosis
– ?
– _____________ _________ can be difficult to treat & may have substantial morbidity / mortality

Back 40

• Diagnosis - biopsy & culture

• Treatment
– Itraconazole 100-200 mg/day x 3-6 mos
– Supersaturated potassium iodine solution (SSKI), amphoteracin B

• Prognosis
– Excellent for cutaneous disease
– Disseminated sporotrichosis can be difficult to treat & may have substantial morbidity / mortality