Systemic Mycoses Flashcards
Systemic Mycoses: Major Themes
Environmental: spores/fungi in soil
Inhaled into lungs
Thermal dimorphism
Wide range of severity: asymptomatic clearance to death
Not person-to-person transmissible
Coccidioides, Histoplamsa, and Blastomyces may mimic TB, but source is American dirt, not foreign crowds
Coccidioides
Dimorphic?
Dimorphic: mold in soil, spherule in tissue (spherule is diagnostic - thick and sturdy)
Grow in the rainy season as mycelia (noninfectious)
In the dry summer, forms hyphae with alternating arthrospores and empty cells
Spores carried by wind and inhaled by humans
Where are coccidioides endemic?
Endemic in southwest US and Latin America; may travel home in returning patient or arrive in contaminated shipped material
Endemic areas are becoming more geriatric: Phoenix and Tucson AZ, Bakersfield and Fresno CA, El Paso TX
Do coccidioides change form in the terminal bronchiole?
They turn into spherules: highly resistant to eradication by the immune system
30 micrometer in diameter
Thick, doubly-refractive wall
Filled with endospores
Wall ruptures to release endospores, develop into new spherules
Spherules and endospores are not infectious - arthrospores are
Coccidioides pathogenesis:
Acute phase
Chronic phase
acute phase - innate immunity (macrophage response) attempts to clear infection, often successful
chronic phase - innate immunity inadequate for clearance; lymphocytes and histiocytes initiate granuloma and giant cell formation (containment)
- if CMI is healthy, infection is contained in granulomas in lung; many eventually cleared asymptomatically
- many patients who become ill have nonspecific flulike symptoms that resolve at home (60% exposures = asymptomatic + flulike)
Coccidioides
if immunosuppressed, disseminated infection both by intracelluar travel in macrophages and hematogenous spread
risk factors: advanced age, immunocompromise, late-stage pregnancy, occupational high-level exposure (farmers, construction workers, archaeologists), black or filipino race
May affect any organ; seen in bones and meninges
induces immune anergy; may be rapidly fatal
localized extrapulmonary infection may result from contaminated injury; usually resolves without treatment
Coccidioides diagnosis:
What season?
Pertinent Hx?
PPD?
-Summer or autumn
-travel or residence in endemic area
-PPD w/ coccidiodin or spherulin
positive if exposed with cleared or contained infection
negative if unexposed or disseminated infection
Characteristics of contained coccidiodes infection
\+PPD often asymtomatic may have flu like illness (fever, cough) 50% have lung changes on xray -infiltrates -adenopathy -effusions -nodules resembling malignancy (biopsy) -bronchoscopy may be useful -10% develop erythema nodosum (adults)/ multiforme (peds) or arthralgias
What is erythema nodosum associated with
Coccidioides contained infection
- “desert bumps” (hypersensitivity reaction)
- red, tender nodules on exterior surfaces like lower legs
- delayed cell-mediated hypersensitivity to fungal antigens
- immunogenic complication of granulomatous diseases
- hypersensitivity may also manifest in eye as conjunctivitis
- EN means risk of dissemination is low
Characteristics of coccidioides disseminated infection:
May affect any organ, most commonly: meninges (meningitis): classic symptoms but isidious onset
bone (osteomyelitis)
Skin or lymph node: soft tissue abscesses; hematogenously seeded
disseminates in 1% of general population, 10% of african-american, filipino, late-pregnancy patients, diabetes, pre-existing cardiopulmonary
dramatic sweats, dyspnea, fever, weight loss
erythema nodosum is a good sign
night sweats, dyspnea, fever, weight loss, and chronic cough may also appear in smokers from chronic lung infection (not disseminated)
Coccidioides diagnosis
biopsy - examine for spherules
culture of sabouraud’s agar - 25C = white mold composed of hyphae w/arthrospores (cultures are infectious)
serology = exposure, titers= titer spikes if disseminating - positives are reliable, but some false negatives occur
Coccidioides treatment
high morbidity but low mortality
no treatment required for mild disease - oral azoles may be used
must treat if predisposed to complications - severe immunosuppression, diabetes, Black/Fillipino, cardiopulomary disease (oral azoles) , pregnancy (amphotericin B)
persisting or disseminated = amphotericin B
Histoplasma
What is it known for?
Thermally dimorphic?
Spores?
Where is it found?
The most common systemic mycosis
Thermally dimorphic: mold in soil, yeast in tissue
Forms two types of asexual spores (1)Tuberculate macroconidia Thick walls Fingerlike projections (2)Microconidia Smaller, thin, smooth-walled Infectious
Endemic in patches worldwide; US: Ohio, Missouri, and Mississippi River valleys: acidic damp soil with high organic content; ~80% of people who live there are exposed
-Environmental: soil, esp bird droppings, esp from starlings or bat guano
Excavation of contaminated soil for construction can set off an outbreak
Histoplasma pathogenesis
How does it get into the body?
How does the body handle the infection?
How do the spores cope?
What happens during a high-dose exposure?
Spores are inhaled
Healthy innate immunity asymptomatically kills a low dose (95% of infections), but gets overwhelmed by high
Spores engulfed by alveolar macrophages may survive endocytosis & lysosomal fusion by producing bicarbonate & ammonia; raises pH and inactivates hydrolytic enzymes
Convert to yeasts in macrophages and replicate there
Spread throughout body in macrophages
Healthy CMI, once raised, activates macrophages to kill most intracellular histoplasma, form granulomas around remainder, eventually calcify, contain infection
May see EN during inflammatory response
High-dose exposure may cause pneumonia w/ cavitary lung lesions on primary infection
Very young, very old, immunosuppressed may progress to more severe dissemination
Pancytopenia
Ulcerated lesions on tongue
Histoplasmosis diagnosis
What is pertinent in the history?
Is PPD helpful?
History: residence in or travel to an endemic river valley, occupational exposure from soil, birds, bats, immune predisposition
PPD not useful: too many false positives and negatives
Mild cases are nonspecific flulike; disease is usually self-limited, findings minimal, may include EN or EM
If spreading in lungs, Cough, chest pain, hemoptysis, ARDS, cavitary lesions
Characteristics of histoplasma - disseminated disease
Disseminated disease: Tongue lesions Granulomas in liver and spleen (sonogram) Weight loss (geriatric) Cardiac: endocarditis, disrhythmia GI: lesions, mass Ocular: scars in back CNS: mass lesions, meningismus, cranial nerve deficits
Histoplasma diagnosis: lab
What would you find on tissue biopsy?
Culture sputum, blood, bronchoalveolar lavage, CSF
Tissue biopsy or bone marrow aspirate for histology: oval yeast cells within macrophages
Bloodwork: pancytopenia in disseminated
Two cultures on Sabouraud’s agar (thermally dimorphic):
25C: tuberculate macroconidia
37C: yeasts
ELISA for histoplasma
polysaccharide antigen
DNA probes for histoplasma RNA
Serologic tests for antibody titers can be useful, but may cross-react w/ other fungal infections, or turn negative in immunosuppressed
Treatment for histoplasma
No treatment required for mild cases: monitor progress
If spreading in lung, oral itraconazole 6-12 weeks
If disseminated, amphotericin B: must use liposomal if any kidney problems, follow w/ 1yr itraconazole
If meningitis, fluconazole (penetrates spinal fluid well)
Blastomyces
Dimorphic?
What is the infectious part?
Where is it found?
Dimorphic fungus
Mold form is hyphae w/ small pear-shaped conidia; conidia infectious by inhalation
Yeast form is round w/ doubly refractive wall and a single broad-based bud
Endemic in eastern North America and Great Lakes region, has also been seen elsewhere : Most common in the US
Grows in wet, rich soil
Blastomyces pathogenesis
What is inhaled?
Where is the virulence factor found?
Infection by inhalation of conidia
Monocytes, macrophages, neutrophils readily kill conidia but once yeast conversion takes place begin to slow down
Virulence factor: Yeast, not mold, produce immune-modulator BAD1 on cell surface
~50% Asymptomatic infection : successful clearance
Most of remainder contain infection with granulomatous response, may develop pulmonary symptoms in process (~45 days post exposure)
Immunosuppression or preexisting pulmonary disease predispose to dissemination, hematogenous seeding of many possible sites
Untreated symptomatic cases have significant mortality (~~40%)
Blastomyces: Diagnosis
Mild form: nonspecific flulike illness, resolves spontaneously
Pneumonia: high fever, chills, cough w/ mucopurulent sputum, pleuritic chest pain, occasionally EN
Chronic illness: looks like TB: pulmonary symptoms w/ weight loss, night sweats, hemoptysis
Fast, severe form: ARDS w/ fever
Any may also include slow development (months-years) of skin lesions, bone/joint pain
Chest Xray is abnormal but variable
Bronchoscopy with needle biopsy may be useful
Blastomyces Diagnosis Lab
Sputum microscopy (KOH mount) 75% diagnostic in patients w/ pneumonia
Tissue biopsy from skin or lung: stain with periodic acid-Schiff or silver, not H&E: thick-walled yeast cells with single, broad-based buds, microabscesses, suppurating granulomatous rxn, not caseating.
Culture from sputum or biopsy: hyphae w/ small pear-shaped conidia
Exoantigen testing and DNA probe tests are available for cultures
PPD and serology are inadequately specific
Blastomyces treatment
Symptomatic but not severe: itraconazole
Severe (including any CNS): amphotericin B, may switch to itraconazole after improvement
Fluconazole also appropriate for meningitis
Surgical excision of loci
Paracoccidioides
Dimorphic?
Paracoccidioidomycosis (PCM), South American blastomycosis, Lutz-Splendore-Almedia disease
Paracoccidioides brasiliensis
Dimorphic fungus:
Mold form has thin, septate hyphae
Yeast form is thick-walled w/ multiple buds
Endemic to rural Latin America
Paracoccidioides pathogenesis
How is the disease transmitted?
Spores are inhaled
Early lesions occur in lungs
Asymptomatic infection common
More severe infection includes oral mucous membrane lesions, lymph node enlargement
Dissemination is possible if immunosuppressed (CMI) or untreated for years
Cutaneous infection is possible from minor injuries with spore-coated wood
Total untreated mortality 16-25%
Paracoccidioides diagnosis: exam
Most common in adult men
History of agricultural work, malnutrition, smoking, alcoholism, immunocompromise
Chronic adult form: much more common (80-90% of cases)
Less severe
Very long latency period (up to 30yrs) followed by endogenous reactivation
Pulmonary symptoms: cough, dyspnea, malaise, fever
Weight loss
Oral lesions
Skin lesions
Lymphadenopathy: many include draining fistulas
Nonspecific immunogenic symptoms
Less common: adrenal glands, long bones, CNS
Paracoccidioides diagnosis lab
What samples do you use and what are you looking for?
What happens wen you culture on Sabouraud?
Is serologic testing useful?
Is skin testing useful?
Is CSF smear helpful?
Pus or tissue samples: KOH mount for yeast cells w/ multiple buds
Stain biopsies with silver for yeast cells, adult form also granulomas
Culture on Sabouraud takes 2-4 weeks
Serologic testing not available outside endemic area
Skin test not helpful
CSF smear is seldom helpful
Paracoccidioides treatment
Oral itraconazole for six months
May use IV Amphotericin B initially if presentation unusually severe; switch to oral azole after improvement
In combination with: correction of anemia, improved diet, rest, cessation of smoking and alcohol.
Paracoccidioides is more opportunistic than the other systemic mycoses in this lecture.
