Fungi/Fungal Diseases

Mycoses

Diseases caused by fungi

Typical manifestation of fungal infections

subacute or chronic infections that commonly relapse over time

Acute fungal disease is

RARE

Cytoskeleton of fungi

has actin microfilaments and tubulin containing microtubules

Ergosterol

A key component of fungal cell wall, similar to cholesterol in animal cells.

How do many antifungal agents work?

by disrupting ergosterol by binding to it and “punching holes” in the cell wall

Complex polysaccharides found in fungal cell walls

• mannans

• glucans

• chitins

ONLY fungus with a capsule

Cryptococcus

Yeast

• unicellular

• reproduces by budding

  • if buds do not separate → pseudohyphae

Hyphae

Threadlike, branching, cylindrical tubules composed of fungal cells attached end to end

Molds (Mycelia)

Multicellular colonies composed of clumps of intertwined branching hyphae

Spores

Reproducing bodies of molds

Dimorphic fungi

Fungi that can grow as either a yeast or mold, depending on environmental conditions

• most fungi grow as year at body temp

Saprophytes

Fungi that live in and untilize organic matter (soil, rotten vegetation) as an energy source

Fungal dissemination infection are most often acquired by

inhalation of conidia

Local fungal infections are most often acquired by

injection (think thorn) past the skin/mucosal membrane

Adherence

• pathogenic factor of fungi

• Yeasts especially can colonize the GI tract and female genital tract

  • Candida best known to adhere to epithelial cells

    • Mannoprotein components extend from the cell wall are adhesins, and interact with host cell fibronectin and others of the extracellular matrix

Adhesions

mannoprotein components of fungal cell walls that promote attachment of fungi to host tissues, facilitating colonization and infection.

Proteases/elastases

• pathogenic factors of fungi

• extracellular enzymes that help promote invasion by breaking down host tissues and evading immune responses.

Most injury during fungal infections is due to

the host's immune response, which can cause tissue damage and inflammation.

Healthy people have

innate immunity to most fungal infections, esp opportunistic molds

How is fungal infection most often cleared from healthy human hosts?

through a combination of the innate activity of neutrophils and through the development of an adaptive, TH1-mediated immune response.

How does humoral immunity effect fungal infections

• it doesn’t

• Antibodies may not corelate with resistance for some fungi

  • Example: High titers of Coccidioides immitis specific antibodies are associated with
    dissemination and a worsening clinical course

however,

Opsonizing antibody is effective for some yeast (Like Cryptococcus and antibodies against its capsule

How does cellular immunity effect fungal infections?

• Very helpful!

• Systemic disease with deficiencies of neutrophils and TH1 immunity increase
  risk for infection, ex:

  • AIDS

  • chronic steroid treatment

  • hematologic malignancies

  • transplant patients

    
    

Fungal Diagnosis

• Direct examination

  • KOH

• Culture

• PCR

• Antigen and Antibody detection

KOH

digests tissues but not fungal walls, allowing for the observation of hyphae under light microscrope with or w/out staining

Sabouraud’s Agar

Ideal agar for culturing fungi

Coccidioides diagnosis

Serum antibodies

Cryptococcus diagnosis

Serum and CSF antigen test

Histoplasma diagnosis

Urine antigen

Superficial fungal infections

• Pityriasis versicolor

• Tinea nigra

Cutaneous fungal infections

• Dermatophytosis

  • infection of the skin

    • tinea corporis

    • tines cruris

    • tinea pedis

  • infection of the hair : tinea capitits

    • infection of the nail : tinea ungulum

• Candidasis of the skin

the ONLY subcutaneous fungal infection

Sporotrichosis

Opportunisitic fungal infection

• Candida

• Aspergillus

• Zygomycetes

• Pneumocystis

Systemic fungal infections

• Cryptococcus

• Histoplasmosis

• Blastomycosis

• Coccidioidomycosis

• Paracoccidiomycosis

Malassezia Fur fur

causes pityriasis (tinea) versicolor

pityriasis (tinea) versicolor

• Caused by Malassezia fur fur

• grows in yeast form in culture media enriched with lipids

• sports seasons

• Tx selenium sulfide shampoo

KOH scraping of tinea versicolor

“spaghetti and meatballs”

Tinea nigra

• Brown to black lesions usually on
  the palms or soles

• Caused by a melanized, black- pigmented fungi, Hortaea werneckii

• It is likely that most patients become infected in aqueous environments (rivers, lakes, and marine areas)

• Florida, North Carolina, and
  South Carolina

  
  

Hortaea werneckii

Causes tinea nigra

Dermatophytes are caused by what three genera?

• Microsporum

• Trichophyton

• Epidermophyton

Dermatophytes clinical presentation

• slow growing eruptions of the skin

• unsightly but NOT painful

• balance between fungal growth and skin desquamation determines who “wins”

• self limited but some can become chronic

Dermatophytes Transmission

• Close contact with an infected person or animal (yep…the cat!)

• Exposure to detached skin scales or hair containing the organism (fomites)
  may also result in infection

  • Locker room floors, barbershops, hotel carpets, movie theater/airplane seats

Onchomycosis

Fungal infection of the nails

Trichophyton rubrum

Fungi that can cause widespread dermatophyte infection, esp if T-lymphocyte cells are deficient

Tinea Captitis

• “ringworm of the scalp”

• Physical findings can be impressive with a huge inflammatory response

• Commonly you can see a “kerion” form

• Dx: Scrape the leading edge and do KOH mount and look for hyphae

Sporothrix schenckii

• Dimorphic

  • cigar shaped yeast

• Found in hay, moss, potting soil, etc

• transmission: inoculation through the skin, often the finger

Occupations to look out for regarding Sporothrix schenckii

farmers, gardeners, landscapers

Clinical presentation of Sporothrix schenckii

• Development of a nodular lesion that ulcerates

• Multiple subcutaneous nodules appear along lymphatic course, these then suppurate and drain

• can progress to joint involvement if not treated properly!

General characteristics of opportunistic fungal infections

• Grow in multiple morphologic forms, most often budding yeast

  • Can form hyphae-like structures (germ tubes)

    • Can do this in the presence of serum (which generally only Candida albicans does)

    • Germ-tube negative strains may be further identified biochemically as reported as “yeast
      not C. albicans”

  • Other elongated forms with restrictions at regular intervals are called pseudohyphae because they lack the parallel walls and septation of true
    hyphae.

Candida Albicans

• infection Occurs commonly in the oropharyngeal, gastrointestinal, and female genital tract

• Risk factors

  • Indwelling IV catheters

  • Indwelling urinary catheters

  • Prolonged use of antibiotics

Pathogenesis/Immunity of Candida Albicans

• One of the most important aspects of its ability to cause pathology is the ability to form biofilms

  • The biofilms adhere to surfaces and inhibit immune cell function and antifungal
    penetration

• Antibiotics and immunosuppression increase risk markedly

• T-lymphocytes are very important (thus in AIDS, etc. a big problem)

Thrush

• Oral manifestation of C. Albicans

• Scrapping the fungal plaque with a tongue blade will show underlying mucosal invasion and inflammation

Vulvovaginal Candidasis

• Clinical manifestation of C. Albicans

• presents with thick, curd-like vaginal discharge and
  itching

• Found in Skin folds and other moist areas in the groin, under the breast, DIAPER AREA!

C. Albicans Esophagus and upper GIT lesions

• Clinical manifestation of C. Albicans

• most common in AIDS and immunocomp patients

• presents as painful swallowing or substernal chest pain

C. Albicans in the uninary tract can cause

• Cystitis, pyelonephritis

• Most commonly in hospitalized patients or those with urinary catheters

C. Albicans in Disseminated disease

• Very high mortality

• Seen in Hospitalized patients

  • burns

  • IV caths

  • GI alterations

  • Colonized prosthetic devices with candida

Endophthalmitis with Candida

• ALWAYS check for this in those with Candidemia, as it is very common!

• White cotton ball expanding on the retina or floating free in vitreous humor

Aspergillus

• Rapidly growing

• Seen most often in patients with severe immunocompromising positions

• In culture and during infection grows as branching septate hyphae

• Picture shows its asexual, conidium-forming structure, which is unique to this organism

Apsergillus epidemiology and pathogenesis

• infection Most commonly caused by inhalation

• Once inhaled, this species is small enough to reach the terminal airways and alveoli

  • RARE for healthy individuals to get infection to to innate immune cell protection

Host factors that increase risk of Aspergillus infection

• Bronchiectasis

• Severe emphysema

• Neutropenia

• Lung transplantation

First line of defense against Aspergillus

Pulmonarly alveolar macrophages, which phagocytose and kill this fungus prior to germination

Which fungal infection do AIDS parients rarely get, suggesting T-cell mediated immunity is less important than innate immunity in preventing infection

Aspergillus

4 main ways Aspergillus affects human hosts

1. Aspergillus pneumonia

2. Disseminated aspergillosis

3. Allergic respiratory disease

4. Aspergilloma (fungus ball)

Aspergillus Pneumonia

• Lung is primary organ involved

• In normal humans, immune responses are usually able to clear spore before infection

• In those with anatomic defects: Emphysema and bronchiectasis (cystic fibrosis) have regions within their lungs that offer protected sites for fungal germination and growth

  • “smoldering” infection can result in symptoms of chronic bronchopneumonia with flares of cough
    and worsening respiratory function

• In those with immune defects: Develop a progressive and immediately life-threatening pneumonia without necessary anatomic problems

Disseminated Aspergillosis

• After a primary infection in immunocomp patient, fungus disseminates into to the bloodstream to go anywhere in the body

• Scariest site to spread: Central nervous system

• High mortality

Allergic Respiratory Disease

• In patients, with allergic tendencies, the accumulation of excess mucus in the areas may provide a growth substrate for inhaled Aspergillius

  • However, as potent allergens, the fungi may induce a cycle of progressive
    inflammation creating mucinous substrate for fungal growth.

  • May grow in the sinuses and larger airways and cause chronic allergic symptoms

• Children with asthma are particularly prone to a condition called allergic bronchopulmonary aspergillosis (ABPA)

Aspergilloma (fungus ball)

• Patients with prior lung infections can develop pulmonary scarring and cavities

  • Fungal spores could grow in these cavities and make macroscopic fungal colonies

• Can invade but instead induce mechanical trauma

  • They literally roll around in the cavity!

  • Cause hemoptysis but if near large blood vessels can cause life-threatening bleeding

Aspergillus Diagnosis

• Can be found in cultures of infected tissues, BUT

• The problem is distinguishing colonization with true invasive disease

• Bronchoalveolar lavage (BAL) or lung biopsy is commonly required

• Aspergillus serology can be helpful in ABPA but not invasive disease

Zygomycetes (Mucormycosis)

• Highest risk of infection in:

  • Neutropenia

  • DM

  • Immunosuppresed pts on corticosteroid therapy

• Inhalation is most common route of infection

• Best known for causing rhinocerebral mucormycosis

Rhinocerebral Mucormycosis

• When Zygomycetes (Mucormycosis) Penetrates the sinuses, palate and invade to the base of the brain!

• Classic is diabetic with a bloody nose or nasal stuffiness on one nares and when you look in
  there you see a black necrotic area

• Tx: Extensive surgical debridement with high dose antifungal therapy

Pneumocystis jirovecii

• Common colonizer of the human airway

• Lethal in AIDS patients with <200 CD4+ cell counts

• 75% are infected by age 4, but Alveolar macrophages clear the infection

  • In healthy ppl, CD4 cells cause host inflammatory response by recruiting additional immune cells (monocytes, macrophages), which eliminate the organism

Clinical Presentation of Pneumocystis jirovecii

• AIDS pts w/ < 200 CD4 cell counts

• Dyspnea on exertion

• Elevated plasma levels of 1-3-beta-D-glucan (component of cell wall)

• On high resolution computed tomography (НRСТ), ΡJР pneumonia typically manifests as bilateral patchy or nodular ground glass opacities

Diagnosis of Pneumocystis jirovecii

• Induced sputum or bronchoalveolar lavage (BAL) with DFA or PCR or Gomori-methenamine silver stains

• If beta-D-glucan test is available, it can help distinguish colonization versus true infection in patients with atypical clinical presentations.

Treatment of Pneumocystis jirovecii

TMP/SMX for 21 days

Prophylaxis for those with AIDS and CD4+ < 200 cells

Cryptococcus neoformans

• life cycle involes asexual and sexual forms

• Identitifcation involves the identification of the enzyme phenol oxidase, which is solely produced by this fungus

Histo identification of Cryptococcus

• methenamine silver stain

• Mucicarmine stain highlights both the yeast form and the
  capsule and is specific for this fungus

• Fontana-Masson stain reveals melanin
  contained in the yeast

Cryptococcus capsule

• Visualized using india ink

• has antiphagocytic properties and is an important virulence determinant

Phenol oxidase

• unique to C. Neoformans

• catalyzes one step in the conversion of phenolic compounds to melanin
  

Most patients with cryptococcus are

Immunocompromised

• AIDS

Cryptococcus in AIDS patients

• Disseminated infection is a serious opportunistic infection that occurs in patients with AIDS with CD4+ count < 100 cells/microL

• meningitis is the most frequently encountered manifestation among those with
  advanced immunosuppression

• Symptoms of cryptococcal meningoencephalitis typically begin indolently over a period of 1-2 weeks.

  • The most common symptoms are fever, malaise, and headache

  • “worst HA of their life”

• ~6% present with focal neurologic deficits, such as CN palsies.

• Others present with tachypnea and skin lesions resembling molluscum contagiosum.

Dx of Cryptococcus

• MRI or CT scan of the Head is done first to make sure not increased intracranial pressures

• Spinal tap (lumbar puncture, LP) is mandatory to make the diagnosis

Histoplasma Capsulatum

• Themrally dimorphic fungus

  • This is how it gains entry into humans via inhalation of this environmental spores

  • can become chronic or disseminated in some competent and commonly in immunocompromised (AIDS)

• Risk Factors

  • Chicken coops or farm buildings with large accumulations of bird droppings, bird roost sites, caves

  • Excavation/construction/demolition/remodeling

Macrophages initially injest but do not kill what fungus?

Histoplasma capsulatum

Time frame of cellular immunity to Histoplasma Capsulatum

10-14 days after exposure

Symptoms of Histoplasma Capsulatum

• 2-4 weeks after exposure develop Fever, chills, headache, myalgias, anorexia, cough, and chest pain

• Chest pain is substernal and often is aggravated by deep inspiration; patients may experience pleuritic pain

• Coryza and sore throat are NOT typical and should suggest alternative diagnoses.

CXR of histoplasma capsulatum

• Enlarged hilar or mediastinal lymph nodes with focal infiltrates but may be normal.

• Calcification of mediastinal nodes or lung lesions are seen within a few months in children, but calcification usually takes several years to develop in adults.

Blastomyces Dermatitidis

• Has thermal dimorphism

  • mold at room temp

  • yeast at body temp

  • due to hybrid histidine kinase

• Transmission:

  • Inhalation of conidia

  • PMNs can ingest conidia and kill 50%

  • In contrast, yeast forms are more resistant to phagocytosis and killing.

  • PMNs can only kill 20% of yeast, which are generally too large for ingestion

  • Conidia, the infectious stage, are converted to the yeast phase in tissue.

  • This conversion results in a survival advantage , which contributes to infection

Virulence Factor of Blastomyces Dermatitidis

• Conversion to the yeast form induces the expression of an essential virulence factor, BAD-1.

• BAD-1 is expressed on the cell surface and is released into the extracellular matrix.

• BAD-1 functions as an adhesin that can bind to CR3 and CD14 of macrophages

BAD-1

Essential virulence factor of B. Dermatitidis

Host defense of B. dermatitidis

• The major acquired host defense is cellular immunity

• Mediated by antigen-specific T lymphocytes and lymphokine-activated macrophages.

• Antibody production appears not to provide protection

B. Dermatitidis outbreaks/epidemics are often associated with

Waterways

• Highway construction near waterways

• Paper Mill

• Beaver dams (bulldozing them and Scouts deconstructing them)

blastomyces dermatidis isolated infection risk

Pet dogs who have pneumonia and die or have known blastomycosis!

Clincal Manifestation of Blastomycosis

• Asymptomatic infection (50%)

• Acute pneumonia

• Chronic pneumonia

• Extrapulmonary disease

• 3-6 week incubation period for pulmonary disease

• Extrapulmonary symptoms have variable incubation periods

• Reactivation (both with pulmonary and extrapulmonary
  symptoms) can occur in immunocompromised (taking TNF-alpha inhibitors or steroids)

Sites of infection of Blastomycosis

• Pulmonary - 91%

• Skin - 18%

• 17% had 2 or more sites of infection

Dx of Blastomycosis

Urine antigen and try to get sputum or lung specimens for direct microscopy, culture, and histopathology

Coccidiodes immitis

• Infection is usually acquired by inhalation of arthroconidia

• The cellular immune response is important

• Causes pulmonary lesions that are characterized by caseating granulomata with an active T-cell response

Coccidioidomycosis—Disease Manifestations

• Asymptomatic infection

  • Dx is usually a part of screening due to immunocompromised or pulmonary disease evaluation

• Primary Coccidioides Pneumonia (AKA Valley Fever)

• Extrathoracic Nonmeningeal Disease

• Meningitis

Primary Coccidioides Pneumonia (AKA Valley Fever)

• Incubation: 7-21 days after an exposure

• Localized pneumonia

• Rheumatologic → arthralgias

• Skin → erythema nodosum

• Dx: IgM and IgG serologic EIA tests

  • Immunodiffusion tests are then performed to confirm initial EIA positivity

• Tx: Fluconazole

• Risk of Reactivation if become immunocompromised in the future

Extrathoracic Nonmeningeal Disease

• Clincal manifestation of Coccidioidomycosis

• Lesions become evident within weeks to months after initial exposure

• Skin or subcutaneous soft tissue

• Osteoarticular involvement

• Vertebral infection

• Tx: Fluconazole/other meds with surgical debridement