Deep Fungal Disease

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Fungi

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Eukaryotic organisms with nucleus, nuclear membrane, ER, & mitochondria
~80,000 species of which <400 (<0.5%) are medically important
<50 species cause >90% of human infections

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Invasive fungal infections

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(deep fungal infections or deep mycoses)→Infections that involve internal organs (skin +/- involved)

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Filamentous fungi (moulds)

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Grow as multinucleate, branching hyphae, forming a mycelium; undergo asexual reproduction

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Yeast

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Grow as ovoid or spherical single cells that multiply by budding & division

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Dimorphic fungi

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Form hyphae at environmental temperatures (25 degrees C) but grow as yeast in the body (37 degrees C)
I.e. Blastomyces, coccidiodes, histoplasma

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Invasive Fungal InfectionsEpidemiology

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Many of the fungi that cause human disease are free-living organisms in the environment (e.g. Aspergillus) that may be acquired by inhalation, ingestion, or inoculation thru the skin; certain of these fungi have a very restricted geographic endemicity (e.g. Coccidioides)→Exogenous in origin
Some fungal pathogens are part of the normal human flora (e.g. Candida) & invade when host defenses become impaired→Endogenous in origin
Human to human transmission is uncommon

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Invasive Fungal Infections Incidence

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Population of pts at risk for IFIs has expanded dramatically over past 20 yrs
-Aggressive chemoRx of malignancies
-Increasing #’s of transplants
-Expanding usage of immunosuppressive Rxs
-HIV epidemic
-Increasing encroachment of humans into sylvan habitats
As a consequence, incidence of, & mortality due to, IFIs has significantly ↑’ed

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IFIs: Endemic Mycoses

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Blastomycosis
Histoplasmosis
Coccidioidomycosis
Sporotrichosis
Paracoccidioidomycosis

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Invasive Fungal Infections
Diagnosis

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Epidemiology
Clinical features
Radiographic findings
Histopathology
-Potassium hydroxide (KOH)
-Gomori methenamine silver (GMS)
-Periodic acid-Schiff (PAS)
Culture
-Sabouraud’s agar
-Brain heart infusion agar
Serology or antigen detection

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Blastomycosis
Clinical Features

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Majority of infected pts manifest symptomatic clinical disease (≥ 90%)
Causes an acute or chronic pneumonia
May disseminate to skin, bone, GU tract, or liver
Mimics malignancy (esp. lung and skin)

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Blastomycosis
Epidemiology

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Endemic to southeastern/south central US, the Great Lakes region, & near St. Lawrence River
Acquired via inhalation during outdoor activities near decaying vegetation, moist soil, or body of water

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Blastomycosis
Diagnosis

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Smears & histopath
-Broad-based budding yeasts with thick refractile walls (KOH, GMS, PAS)
Culture
-Sabouraud dextrose agar→Grow as a mould
Serology
-Not reliable
Antigen detection
-Emerging utility as diagnostic test; serum & urine

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Blastomycosis
Treatment
Severe disease

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Amphotericin B

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Blastomycosis
Treatment
Mild to moderate disease

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Itraconazole (fluconazole)

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Blastomycosis
Key Teaching Points

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Dimorphic fungus
SE & south central US & Great Lakes area
<10% asymptomatic : >90% symptomatic
Chronic pneumonia; skin
Broad-based budding yeast
No useful serology (? serum antigen)
Amphotericin or itraconazole

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Histoplasmosis
Epidemiology

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Endemic to Ohio & Mississippi River valleys, Mexico, & Central America
Acquired via inhalation of conidia during dust storms or building renovation or near large quantities of bird or bat guano in caves

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Histoplasmosis
Clinical Features

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Majority of infections asymptomatic; 10% of patients have clinical disease
Chronic pneumonia; mucosal ulcers
Disseminated infection +/- CNS involvement in the compromised host

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Which fungi grows readily in bird/bat droppings?

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Histoplasmosis

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Histoplasmosis
Diagnosis

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Smears & histopath→Ovoid 3-5 µm yeasts with narrow-based budding; often within macrophages; seen best with GMS
Culture→Sab; grows as mould
Serology→Comp fix
Antigen detection→Mainstay of dx; urine > blood; sensitivity 75+%
Skin testing→Useful for epi not clinincal dx

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Histoplasmosis
Treatment

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Majority of pts require no Rx (remember it is asymptomatic)
Severe disease
Amphotericin B
Mild to moderate disease
Itraconazole or fluconazole

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Histoplasmosis
Key Teaching Points

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Dimorphic fungus
Mississippi & Ohio River valleys
90+% asymptomatic : <10% symptomatic
Pneumonia; disseminated infection
Small yeast often within macrophages
Serum and urine antigen assays
Amphotericin or itraconazole

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Coccidioidomycosis
Epidemiology

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Endemic to southwestern US (epicenter in south central Arizona), Mexico, & S. America→Travel hx
Inhalation of arthrospores when arid, sandy desert soil is disturbed→Military maneuvers in the desert; archaeological digs; off-road riding, etc

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Coccidioidomycosis
Clinical Features

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60% of infxns asymptomatic
Acute or chronic pneumonia
Disseminated disease→Skin, bones and joints, CNS
Erythema nodosum

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Coccidioidomycosis
Diagnosis

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Smears & histopath→Spherules & endospores
Culture→Grows on routine media as well as Sab→Mould
Serology→Comp fix useful in predicting dissemination (1:16)
Antigen detection→Under developement
Skin testing→Useful as epidemiologic tool

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Coccidioidomycosis
Treatment

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“Uncomplicated” pneumonia
-“Watchful waiting” (predictors of progression) or itraconazole
Progressive pneumonia or disseminated infection
-Amphotericin B or itraconazole
CNS infection
-Amphotericin B or fluconazole

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Coccidioidomycosis
Key Teaching Points

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Dimorphic fungus
Southwestern US
60% asymptomatic : 40% symptomatic
Pneumonia; CNS infection
Spherules and endospores
Complement fixation serology
Amphotericin or itraconazole (fluconazole)

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what fungi has spherules?

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Coccidioidomycosis

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what fungi has broad based attachments?

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Blastomycosis

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Yeasts

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**Candida species**
Cryptococcus
Trichosporon

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Moulds

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(Invasive filamentous fungi)
**Aspergillus**
The zygomycetes
Pseudallescheria/Scedosporium
Fusarium
Others

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Opportunistic Mycoses

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Yeasts and Molds

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Candidiasis
Spectrum of infections

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encompasses cutaneous, mucosal, and deeply invasive disease→Endogenous in origin

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What is the most frequent cause of invasive fungal infections?

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Candida (especially in meutropenic host and surgical ICU pts)
4th most common cause of BSIs in US (7.6%) with an associated crude mortality rate of 40%
25-50% of Candida infections occur in pts in ICUs

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Candidiasis
Manifestations

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fungemia, disseminated disease with multiorgan involvement, or single organ disease

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Candida species

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C. albicans is the most common species causing infection but the non-albicans species are increasing in frequency
-? Greater risk for invasion→dissemination
-Higher incidence of antifungal drug resistance
--C. glabrata→30% resistant to fluconazole
--C. krusei→91% resistant to fluconazole

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Candidiasis
Spectrum of infections

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encompasses cutaneous, mucosal, and deeply invasive disease→Endogenous in origin

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What is the most frequent cause of invasive fungal infections?

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Candida (especially in meutropenic host and surgical ICU pts)
4th most common cause of BSIs in US (7.6%) with an associated crude mortality rate of 40%
25-50% of Candida infections occur in pts in ICUs

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Candidiasis
Manifestations

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fungemia, disseminated disease with multiorgan involvement, or single organ disease

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Candida species

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C. albicans is the most common species causing infection but the non-albicans species are increasing in frequency
-? Greater risk for invasion→dissemination
-Higher incidence of antifungal drug resistance
--C. glabrata→30% resistant to fluconazole
--C. krusei→91% resistant to fluconazole

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C. glabrata

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30% resistant to fluconazole

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C. krusei

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91% resistant to fluconazole

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Candidiasis
Risk Factors for Invasive Infection

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Central venous catheters
Exposure to the ICU
Hemodialysis
Documented mucosal colonization
Parenteral hyperalimentation
Systemic antibiotics
Abdominal surgery
Neutropenia >1 wk
Immunosuppressive therapy

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Candidiasis
Diagnosis

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Identification of “typical” clinical features
Biopsies of involved tissues that reveal yeast and/or pseudohyphae
Cultures of blood or involved tissues
NO useful serologies or antigen detection techniques

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Candidiasis
Treatment

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Amphotericin B (or lipid formulations), azoles (fluconazole, itraconazole, voriconazole), or echinocandins (caspofungin, micafungin, anidulafungin)
Choice of agent and duration of Rx dependent upon type disease, severity, & causative species

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Treatment changes of Candidiasis

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Past: Amphotericin B
Currently: Fluconazole or echinocandins

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Candidiasis
Key Teaching Points

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Yeast
Normal human flora (GI, skin)
Colonizer or pathogen
Associated with ↓PMNs, ↓CMI, or ICU stay
Mucosal disease; fungemia; visceral abscesses
Yeast &/or pseudohyphae
No useful serologies; culture of blood or tissue
Amphotericin, azoles, echinocandins

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Aspergillosis

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most common form of invasive filamentous fungal disease (IFFD) in humans, with A. fumigatus the most common causative agent (Property of angioinvasion)

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Angioinvasion is associated with what fungus?

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Aspergillus
(it causes ischemic injury and necrosis)

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Aspergillosis
Transmission

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Inhalation of airborne spores is the usual route of infection (exogenous in origin)→Pneumonia is most common type of IA (>50% of pts)
Almost all pts with IA have an underlying immunocompromising condition (98%); < 5% of disease occurs in “normal hosts”

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Pulmonary Aspergillosis

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Allergic bronchopulmonary aspergillosis
Aspergilloma (fungus ball)
Semi-invasive (chronic necrotizing) aspergillosis
Invasive pulmonary aspergillosis

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Invasive Pulmonary Aspergillosis (IPA)

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Rapidly progressive disease, often disseminated, occurring in markedly immunocompromised pts, esp those with prolonged & severe neutropenia
Classic radiographic findings include a pleural based infiltrate, the “halo” sign (90%), or the “air-crescent” sign (~60%)
Organisms may or may not be demonstrable in sputum or bronchoalveolar lavage fluid specimens

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Invasive Aspergillosis
Diagnosis

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Clinical features and radiographs may suggest diagnosis but are not definitive
Whenever possible, dx should be based on compatible tissue histo + positive cx
Remember that tissue histology alone is not specific for Aspergillus
Serum antigen detection (galactomannan) is an evolving diagnostic test

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Invasive Aspergillosis
Treatment

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Primary Rx of proven or probable dz
-Voriconazole
Salvage Rx for non-responders
Lipid formulation of -Amphotericin B
-Caspofungin (Micafungin)
-Itraconazole
-Combination therapies
Role of surgery w/pulmonary & sinus dz

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Aspergillus Histology

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Acute angle (less than 90 degrees) branching
Septated

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Aspergillosis
Key Teaching Points

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Mould
Ubiquitous in the environment→Spore
Opportunistic pathogen→↓PMNs>↓CMI
Pneumonia>sinusitis>other
Septated hyphae w/ acute angle branching
Galactomannan antigen assay
Rx: Voriconazole>Ampho>Caspo or Itra

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"air cresent" sign

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in radiography of the lung, a crescent of gas near the top of a mass lesion, signifying cavitation with a space above the debris; seen in aspergilloma, hydatidoma