Fungi Fascination

HUMA SAEED, MBBS, FRCPC

ASSISTANT PROFESSOR OF MEDICINE
DIVISION OF INFECTIOUS DISEASES | IMMUNOCOMPROMISED ID
WESTERN UNIVERSITY
Disclosures

 None
Objectives

 Introduction
 Morphology
 Pathogenesis
 Antifungal Targets
 Classification of Fungi
 Epidemiology
 Disease Spectrum
 Diagnosis
 Treatment / Management
Introduction: All About the Bug

 Eukaryotic organisms – closer to animals than plants (crabs, lobsters).

 Cell-wall is composed of chitin.
 Major environmental decomposers.
 Plastic car parts, synthetic rubber and lego are made using itaconic acid
derived from a fungus, Aspergillus terreus.
 Fifteen percent of vaccines and therapeutic proteins are made in the
yeasts (Hep B vaccine).
 Medicinal properties – penicillin, statins.
 Largest living organisms on earth is a fungus – Honey Mushroom in Oregon
Introduction: All About the Bug

 They can create Zombie Ants

 Ophiocordyceps unilateralis infects the ants and control their brains
Morphology

• Cell membrane: bilayer

membrane – made of ergosterol

• Cell wall – comprises of chitin and

glucans.
Morphology

 Hyphae– long, branching filamentous structures. Individual cells

may or may not be divided by septations.
 Mycelium / mycelia – collection of hyphae
 Pseudohyphae – long, branching structures. Intermediate between
chain of budding cells and true hyphae. Cytoplasmic connections
present between individual cells.
 Conidia – type of reproductive spore at the tip of the hyphae
 Spores - ‘fungal seeds’ ; produced from the fungal hyphae
Morphology
 Pathogenesis

 Most are opportunistic infections

 Fungal overgrowth (antibiotic use with candida)
 Compromise in the immune system
➢ First line of defense – mucosal barriers and skin
(Blastomyces, candida)
➢ Second line of defense – neutrophils (mold)
➢ Third line of defense – cell mediated immunity
 High inoculum load can overcome immune defenses
 Endemic fungi – respiratory acquisition
Antifungal Targets

➢ Ergosterol in the fungal cell membrane

➢ Azoles inhibit fungal cytochrome P450 3A-dependent C 14-
demethylase which converts lanosterol into ergosterol.
➢ Amphotericin forms a complex with ergosterol and pokes holes
in the fungal cell membrane.
➢ 1,3 D-glucan in the fungal cell walls
➢ Echinocandins inhibit glucan synthesis.
➢ Not present in mucor spp – hence not effective
Classification of Fungi

Yeast Dimorphic fungi Mold

Sporothrix Aspergillus
Candida
Histoplasma Rhizomucor
Cryptococcus
Blastomyces Fusarium
Saccharomyces
Coccidioides Microsporium
Trichosporon
Paracoccidioides Trichophyton
Penicillium Scedosporidium
Classification of Fungi

Yeast Dimorphic fungi Mold

Sporothrix Aspergillus
Candida
Histoplasma Rhizomucor
Cryptococcus
Blastomyces Fusarium
Saccharomyces
Coccidioides Microsporium
Trichosporon
Paracoccidioides Trichophyton
Penicillium Scedosporidium
“ YEAST

Candida spp and

Cryptococcus spp.
”
Case

 Thirty-one year old female comes in with

urinary urgency, burning micturition and
lower abdominal cramps for five days. She is
otherwise afebrile and systemically well. Her
urine dipstick shows pyuria and bacteruria.
Urine culture is sent out and she is prescribed
a five-day course of TMP-SMX (Septra)
empirically.
 Two days later she returns and reports
resolution in the urinary symptoms. However
she now has oral burning and whitish lesions
on the buccal mucosa and tongue
Candida spp.

EPIDEMIOLOGY
 Unicellular fungi, endosymbionts in humans; live in GI and GU
tract.
 Most common cause of fungal infections worldwide.
 Antibiotics promote overgrowth.
 Comprise of 200 species, but only some cause infections.
 Candida albicans – dimorphic fungus
Candida spp.

EPIDEMIOLOGY
 Notable species:
 C. albicans: most common
 C. kruseii and glabrata: azole-resistant, dose dependent
 C. parapsilosis, guilliermondii: echinocandin-resistant
 C. lusitaniae: Amphotericin-resistant
 C. auris: can be pan-R
Candida spp.

DISEASE
 Typically cause opportunistic infections or in the setting of
antibiotic use – oral thrush, esophageal, vulvovaginitis, rarely
UTIs.
 Invasive infections in immunocompromised hosts and stem cell
transplant recipients
 bloodstream infections, endocarditis
 Hepatosplenic candidiasis
 Catheter associated infections
Candida spp.

DIAGNOSIS
 GS – gram positive oval budding yeast cells with pseudohyphae.
 Silver stains, KOH stains
 Specimen and blood cultures.
 Immunodiagnosis, Ab/AB detection against cell-wall mannan.
Candida spp.

MANAGEMENT
 Azoles: fluconazole first-line if susceptible. Higher doses of other
azoles in case of DDR.
 Echinocandins: typically first choice for invasive infections until
susceptibility returns.
 Dual therapy with azoles and echinocandins for endocarditis.
 Amphotericin: usually reserved for invasive infections unresponsive to
first-line therapy.
 Removal of catheter/hardware.
Cryptococcus spp.

EPIDEMIOLOGY
 Two major pathogenic species: Cryptococcus neoformans and
Cryptococcus gattii.
 neoformans: found in pigeon guano and rotting trees
 gattii: found in eucalyptus and coniferous trees
 Can colonize humans without causing disease
 One million new cases of cryptococcosis per year, more than
600,000 deaths worldwide annually.
Cryptococcus spp.

DISEASE
 Risk factors: AIDS, corticosteroid treatment, transplantation,
cancer, sarcoidosis, lymphopenia, cirrhosis.
 Major sites: CNS (meningoencephalitis but sometimes
ringed lesions – cryptococcoma) and lungs (cavitary,
nodular, interstitial pneumonia)
 Other sites: skin, prostate, peritoneum and eye
Cryptococcus spp.

DIAGNOSIS
 Serum cryptococcus Ag (sens: 99%, sp: 94%)
 CSF cryptococcus Ag (sens: 98%, sp: 99%)
 Culture of the body site: CSF, blood, pulmonary lavage
 Direct microscopy: India ink and histopathological stains
including mucicarmine
Cryptococcus spp.

MANAGEMENT
 Amphotericin + 5FC
 Fluconazole
 Lifelong suppression is often required in the setting of
ongoing immunosuppression
“ DIMORPHIC FUNGI

Sporothrix spp
Histoplasma spp
Blastomyces spp
”
Coccidioides spp
Common Properties

 Exist in two forms

“yeast in heat; mold in cold”
Mold – multicellular filamentous form better suited for survival in the environment, aids in colonization.
Yeast – helps adapt to host defenses inside the cells, reproduce rapidly.

 Candida albicans is considered a dimorphic fungus as well.

“pseudohyphae in heat”
 Endemic mycoses – not endogenous in humans
 Can cause asymptomatic disease.
 Acquired through inhalation of spores.
Sporothrix spp (shenckii)

EPIDEMIOLOGY
 Worldwide distribution.
 Acquisition associated with exposure to soil, plants and plant-
products (hay, straw etc).
 May be transmitted by cat scratches or bites.
Sporothrix spp (shenckii)

DISEASE
 Sporotrichosis or “rose handler’s disease”.
 Inoculation through puncture wound/cut > formation of
ulcerated nodule at the site of injury > spread through the
lymphatics and appearance of similar nodules along the
lymphatics.
 May be disseminated in immunocompromised hosts.
Sporothrix spp (shenckii)

DIAGNOSIS
 Direct visualization – culture of the swab in Sabouraud agar or
brain heart infusion culture.
 Molecular techniques – rRNA amplification being studied
Sporothrix spp (shenckii)

MANAGEMENT
 Oral saturated potassium iodide
 Itraconazole or terbinafine – local
 Amphotericin for disseminated infection
Histoplasma spp (capsulatum)

EPIDEMIOLOGY
 Distributed worldwide except in Antartica
 Most prevalent in Ohio and Mississippi river valleys, St. Lawrence
Valley, Mt. Royal, St. Thomas, London, parts of Manitoba,
Quebec and Nova Scotia
 Present in bird droppings, bat droppings and soil
 Outbreaks occur while spelunking (cave exploring) or clean bird
coops.
Mold: individual short stalks that readily Yeast: Narrow-budding yeast.
become airborne when the colony is Formed in infected tissues, small (about 2–4 μm) and are
disturbed. characteristically seen forming in clusters within phagocytic
cells, including histiocytes and other macrophages, as well as
monocytes.
Histoplasma spp (capsulatum)

DISEASE
 Localized pulmonary infection:
 Asymptomatic infection or mild pneumonia in immunocompetent
hosts.
 Symptomatic pneumonia – lesions calcify and form granulomas (mimic
TB), found in spleen and lungs.
 Disseminated infection – immunocompromised host, can infect any
organ (liver, lungs, spleen).
 Subacute fever, pancytopenia, hypoadrenalism, mucosal lesions,
military lung lesions
 Oral ulcers
 Granulomatous mediastinitis
Histoplasma spp (capsulatum)

DIAGNOSIS
 Direct visualization through GMS stain – narrow budding yeast
 No capsule despite the name
 Clusters within phagocytic cells, including histiocytes and other
macrophages
 Histoplasma Antigen assay (cross-reacts with Blastomyces Ag)
 Ab test – non specific
 Culture of specimen (blood, BAL, tissue, etc).
Histoplasma spp (capsulatum)

MANAGEMENT
 Itraconazole
 Amphotericin
Blastomyces spp (dermatitidis)

EPIDEMIOLOGY
 Lives in the soil, decaying wood
 Mississippi river valley > extends up North around the Great
Lakes.
 Northern Ontario, southeastern Manitoba, Quebec south of
the St. Lawrence River,
 Africa, Asia
Mold: Forms a network of thread- Yeast: budding yeast cells seen in infected
like mycelium that penetrates the substratum on tissues and bodily fluids are generally relatively
which it grows, and then after 3–5 days of large (c. 8–15 μm) and characteristically bud
growth begins to reproduce asexually with small through a broad base or neck, making them
(2–10 μm) conidia (asexual spores). These highly recognizable to the pathologist.
conidia are probably the main infectious
particles produced by the fungus.
Blastomyces spp (dermatitidis)

DISEASE
 Blastomycosis - Chicago Disease.
 Localized cutaneous infection at the site of inoculation.
 Pneumonia – asymptomatic or symptomatic. Can mimic
cancer occasionally.
 Disseminated infection in immunocompromised hosts – can
affect any site of body (including prostatitis, arthritis).
 CNS infection
Blastomyces spp (dermatitidis)

DIAGNOSIS
 Direct visualization through GMS/PAS stains – broad-based
budding yeast
 Blastomyces Ag assay (cross-reacts with histoplasma ag)
 Ab testing - non specific
 Culture of the specimen
Blastomyces spp (dermatitidis)

MANAGEMENT
 Itraconazole
 Amphotericin B for disseminated infections
 Voriconazole or fluconazole for CNS infections
Coccidioides spp (immitis)

EPIDEMIOLOGY
 Desert areas of SW US and Mexico, but slowly moving north
 Resides in the sandy soils
 Most prevalent in Arizona – 60% cases
 Infections usually occur within dry seasons
Mold: exist as mycelia in the environment. Mycelial cells Yeast: Spherules divide internally by
known as arthroconidia are 2 microns to 5 microns in developing internal septae, which divide the
length and are of the right size to reach the terminal spherule into compartments.
bronchiole when inhaled. Once inside the lung,
arthroconidia undergo remodeling from rectangular to
spherical forms known as spherules.
Coccidioides spp (immitis)

DISEASE
 Coccidioidomycosis – Valley Fever
 Mostly asymptomatic pneumonia
 Symptomatic pneumonia
 Disseminated in immunocompromised hosts – can affect any
organ system, including bones and CNS.
 Erythema nodosum may accompany infection (immunological
response to the infection).
Coccidioides spp (immitis)

DIAGNOSIS
 Direct visualization through GMS stain shows spherules within the
tissues.
 Serological tests
 EIA to IgG and IgM, may be falsely positive
 Immunodiffusion
 Specimen cultures
Coccidioides spp (immitis)

MANAGEMENT
 Fluconazole
 Itraconazole
 Amphotericin
“ MOLD

Aspergillus spp
Rhizomucor spp
Fusarium spp
”
 Case

Fifty-five year old male is being admitted in the

hospital for management of acute myeloid
leukemia and is commenced on induction
chemotherapy (7+3). Ten days after the
chemotherapy, he develops high-grade fevers
and altered mentation. His blood work reveals
pancytopenia (ANC - 0), mildly elevated LDFTs,
but otherwise normal. Blood cultures, urine
culture and respiratory viral swab are negative,
The fevers do not resolve despite broad
spectrum empirical antibacterials given for five
days.
Decision is made to obtain CT A/P and thorax.
CT thorax shows nodular opacities with halo
sign.
 Case

Fifty-five year old male is being admitted in the Bronchoscopy is obtained.

hospital for management of acute myeloid BAL cultures are obtained and show the
leukemia and is commenced on induction following on microscopy.
chemotherapy (7+3). Ten days after the
chemotherapy, he develops high-grade fevers
and altered mentation. His blood work reveals
pancytopenia (ANC - 0), mildly elevated LDFTs,
but otherwise normal. Blood cultures, urine
culture and respiratory viral swab are negative,
The fevers do not resolve despite broad
spectrum empirical antibacterials given for five
days.
Decision is made to obtain CT A/P and thorax.
CT thorax shows nodular opacities with halo
sign.
Common Properties

 Contain hyphae.
 Reproduce through spores.
 Few molds can grow below 4 degC – common refrigerator
temperature.
 Penicillium discovered in 1928 by Fleming > Penicillin Ab.
 Most molds are harmless colonizers, but can cause
disseminated infections in immunocompromised hosts.
 Necrotizing, angioinvasive infections.
Aspergillus spp

EPIDEMIOLOGY
 Derives its name from aspergillum
 Ubiquitous in nature.
 Asymptomatic colonization in human GI
and respiratory tract.
 Septate hyphae
Aspergillus spp

DISEASE
 Respiratory
 Allergic bronchopulmonary aspergillosis
- Asthmatics
- Elevated IgE and IgE aspergillus Ab
- Eosinophilia, + skin test
 Aspergilloma – fungal ball in asthmatics or diabetics
 Angio-invasive aspergillosis – disseminated necrotizing pulmonary infection
 Aflatoxin consumption – liver damage and liver cancer after consuming
A. flavus
Aspergillus spp

DIAGNOSIS
 Direct visualization through GMS: branching hyphae at acute angles.
 Biomarkers – galactomannan
 Aspergillus PCR
 Specimen culture from tissue biopsy or BAL
 Blood cultures – mostly contaminant
Aspergillus spp

MANAGEMENT
 Voriconazole
 Isavuconazole/Posaconazole
 Amphotericin
 High-dose echinocandins
Rhizopus, Rhizomucor, Mucor

EPIDEMIOLOGY
 Called “Black Fungus”.
 Ubiquitous in the environment.
 Inhaled and may set up asymptomatic colonization in the respiratory
tract and GI tract.
 Contains aseptate hyphae
Rhizopus, Rhizomucor, Mucor

DISEASE
 Mucormycosis in immunocompromised hosts and those with diabetes
mellitus (DKA), iron overload, steroid use.
 Sinusitis
 Ophthalmitis, periorbital mucormycosis
 Cavitary pneumonia
 Disseminated disease
 >50% mortality
Rhizopus, Rhizomucor, Mucor

DIAGNOSIS
 High index of suspicion is required.
 Direct visualization through PAS and GMS reveals broad based, ribbon-
like hyphae with right-angle branching.
 Cultures have poor sensitivity but do grow.
 Histopathology remains gold standard.
Rhizopus, Rhizomucor, Mucor

MANAGEMENT
 Amphotericin B
 Oral Posaconazole or isavuconazole
Fusarium spp

 Ubiquitous in nature.
 Weapon of biological warfare in 1930s
 Alimentary toxic aleukia, >60% mortality
 Causes opportunistic infection in immunocompromised hosts.
 Necrotizing pneumonia, sinusitis, skin lesions
 Localized infection – keratitis (contaminated lens solution), local skin nodule
 Specimen culture, blood cultures may be positive
 Characteristic skin rash
 Treatment: Amphotericin + voriconazole combination often used in severe
disease.
“
FUNGAL POTPOURRI ”
Case

Twenty-four year old athlete comes in for evaluation of

itchy spots on the upper back. The spots have been
present for three months.
He denies any other systemic symptoms and feels well
otherwise.
On examination, there are several light colored well-
circumscribed lesions on the upper back with superficial
excoriations.
No other skin rashes appreciated elsewhere.
 Superficial Fungal Infections

 Malassezia furfur
➢ Chronic, superficial infection
➢ Involves the stratum corneum –
outer part of the epidermis
➢ Causes Tinea versicolor
➢ Painless, hypopigmented or
hyperpigmented patches
 Superficial Fungal Infections

 Dermatophytes
➢ >30 species
➢ Chronic infection of stratum
corneum

Tinea corporis (body) Tinea cruris (inguinal folds) Tinea pedis (feet)
Ringworm Jock itch Athlete’s foot
Superficial Fungal Infections

Tinea capitis (scalp) Tinea unguium (nails)

onychomycosis
Summary

 Notable yeasts
➢ Candida – commensal organisms.
➢ Localized infections > disseminated disease
➢ Cryptococcus – not typically endogenous. Opportunistic infections
➢ Meningitis in AIDS, cirrhosis

 Notable dimorphic fungi: Endemic mycoses

➢ Histoplasma, Blastomyces, Coccidioides – respiratory acquisition
➢ Asymptomatic > disseminated disease

 Notable molds:
➢ Aspergillus, rhizomucor, fusarium
➢ Angioinvasive infections
Summary

Molds Posaconazole,
isavuconazole
Rhizomucor
Aspergillus
Voriconazole

Dimorphic fungi Itraconazole

Yeast Fluconazole
huma.saeed@lhsc.on.ca
hsaeed42@uwo.ca