Yeast-Associated Infections

Yeasts cause a spectrum of human diseases that range from colonization to uniformly fatal disease

Invasive fungal disease occurs in at-risk patient populations
- Immunocompromised patients
- Patients on immunomodulatory therapy
- Patients with indwelling devices
- Critically ill patients
Species most likely to cause disease include the following
- Yeasts – Cryptococcus neoformans, Candida spp
  - Emerging infectious yeast agents such as Rhodotorula spp and Trichosporon spp
- Dimorphic fungi – Blastomyces dermatitidis, Histoplasma capsulatum and Coccidioides immitis
Manifestations of infection may occur in one or more body sites

Yeast-Associated Signs and Symptoms – Pulmonary

Risk factors for severe pneumonia and disseminated disease

Risk Factors for Severe Pneumonia and Disseminated Disease
Histoplasma	Young children HIV
Cryptococcus	Sarcoidosis Diabetes mellitus HIV Organ transplantation
Candida	Renal failure Presence of CVC/other vascular-access device TPN administration
Coccidioides	Pregnancy HIV Ethnicity Filipino Native American African American
Blastomyces	Pregnancy Organ transplantation HIV
Trichosporon or Rhodotorula	Severely ill patients (eg, leukemia)

Acute primary pulmonary infection

Acute Primary Pulmonary Infection
Histoplasma	Clinical picture similar to tuberculosis with fever, weight loss and lymphadenopathy
Cryptococcus	Fever Chest pain Cough Sputum Weight loss
Candida	Fever Sputum Pneumonia (rare)
Coccidioides	Clinical picture similar to tuberculosis with fever, weight loss and lymphadenopathy
Blastomyces	Clinical picture similar to influenza
Trichosporon or Rhodotorula	N/A

Chronic pulmonary disease

Chronic Pulmonary Disease
Histoplasma	Calcified nodes Chronic cavitary disease Mediastinal granuloma Fibrosis
Cryptococcus	N/A
Candida	N/A
Coccidioides	Coin lesions (coccidiomas) Cavitary disease (thin walled) Granulomas
Blastomyces	Chronic granulomatous disease (Gilchrist disease)
Trichosporon or Rhodotorula	N/A

Yeast-Associated Signs and Symptoms – Sites Other than Pulmonary

Ophthalmologic

Ophthalmologic
Histoplasma	Uveitis and panophthalmitis Presumed ocular histoplasmosis syndrome Posterior uveitis with choroidal scars Neovascularization/loss of central vision
Cryptococcus	Ocular palsies Papilledema Keratitis Endophthalmitis
Candida	Fungal keratitis Endophthalmitis
Coccidioides	N/A
Blastomyces	N/A
Trichosporon or Rhodotorula	N/A

Otorhinolaryngologic

Otorhinolaryngologic
Histoplasma	N/A
Cryptococcus	Gingivitis Sinusitis Salivary gland enlargement
Candida	Thrush Nasal ulcers Otitis externa
Coccidioides	N/A
Blastomyces	N/A
Trichosporon or Rhodotorula	N/A

Central nervous system

Central Nervous System
Histoplasma	Chronic meningitis Cerebritis and mass lesion
Cryptococcus	Meningitis Intracranial abscesses Spinal granuloma
Candida	Meningitis Diffuse microabscesses in the brain
Coccidioides	Chronic meningitis with indolent course
Blastomyces	Abscesses Meningitis
Trichosporon or Rhodotorula	N/A

Hepatosplenic or gastrointestinal

Hepatosplenic or Gastrointestinal
Histoplasma	Hepatosplenomegaly Chronic granulomatous hepatitis
Cryptococcus	Disseminated yeast infections Hepatitis Peritonitis Nodular/ulcerated lesions of colon
Candida	Disseminated yeast infections Esophagitis Gastrointestinal ulcers Peritonitis Hepatic and splenic abscesses
Coccidioides	N/A
Blastomyces	N/A
Trichosporonor Rhodotorula	N/A

Dermatologic

Dermatologic
Histoplasma	Discrete erythematous skin papules in HIV patients
Cryptococcus	Papules Subcutaneous abscesses Purpura Bullae Ulcers Draining sinuses
Candida	Folliculitis (generalized cutaneous form) Disseminated skin infections Intertrigo Paronychia Onychomycosis Diaper rash Vaginitis Chronic mucocutaneous candidiasis
Coccidioides	Maculopapular to verrucous lesions Subcutaneous abscesses Reactive eruptions (contain no organisms) Erythema nodosum Erythema multiforme Toxic erythema Sweet syndrome
Blastomyces	Verrucous or ulcerative lesions Subcutaneous nodules
Trichosporonor Rhodotorula	Red papular lesions (T) Catheter-related fungemia (R)

Bone

Bone
Histoplasma	Osteomyelitis
Cryptococcus	Osteolytic lesions with soft-tissue abscesses
Candida	Osteomyelitis (most common in spine, wrist, femur, ribs, scapula and proximal humerus) Arthritis
Coccidioides	Osteomyelitis (most common in knees, hands, vertebrae and long bones) Symmetric arthritis (referred to as desert rheumatism)
Blastomyces	Osteomyelitis (most common in long bones, vertebrae and ribs)
Trichosporon or Rhodotorula	N/A

Genitourinary

Genitourinary
Histoplasma	Epididymitis Testicular and prostatic abscesses (rarely symptomatic)
Cryptococcus	Prostatitis Renal abscesses Genital lesions
Candida	Vulvovaginitis Balanitis Papillary necrosis Fungus ball Perinephric abscess
Coccidioides	N/A
Blastomyces	Prostatitis Epididymitis
Trichosporon or Rhodotorula	Hematuria (T) Funguria (T)

Indications for Testing

At-risk patients with suspected disease

Laboratory Testing

Respiratory – acute primary infection

Respiratory – Acute Primary Infection
Histoplasma	Sputum fungal stain Histoplasma EIA serum and/or urine Tissue culture
Cryptococcus	Fungal stain Serum Cryptococcus antigen Culture
Candida	Tissue biopsy specimen showing invasion Tissue culture
Coccidioides	Sputum fungal stain Tissue culture Serum ID
Blastomyces	Sputum fungal stain Serum ID, CF, EIA Tissue culture Antigen (serum, urine) as secondary test
Trichosporon or Rhodotorula	N/A

Respiratory – chronic pulmonary disease

Respiratory – Chronic Pulmonary Disease
Histoplasma	EIA serum or urine Tissue culture Antibody detection
Cryptococcus	CF antibodies
Candida	N/A
Coccidioides	N/A
Blastomyces	Serum CF, ID, EIA
Trichosporon or Rhodotorula	N/A

Central nervous system

Central Nervous System
Histoplasma	Cerebral spinal fluid (CSF) stain and culture Serum Histoplasma antigen
Cryptococcus	India ink Serum Cryptococcus antigen CSF Cryptococcus antigen Culture
Candida	Culture Fungal stain (1-3) beta-D-glucan
Coccidioides	CSF stain and culture CF, ID and ELISA antibodies
Blastomyces	CSF stain and culture CF and ID antibodies, EIA
Trichosporon or Rhodotorula	N/A

Ophthalmologic

Ophthalmologic
Histoplasma	Culture Serum Histoplasma antigen and antibody
Cryptococcus	Culture Serum Cryptococcus antigen
Candida	Culture (vitreous fluid) Blood culture (1-3) beta-D-glucan
Coccidioides	N/A
Blastomyces	N/A
Trichosporon or Rhodotorula	N/A

Otorhinolaryngologic

Otorhinolaryngologic
Histoplasma	N/A
Cryptococcus	Fungal stain Serum Cryptococcus antigen Culture
Candida	Culture Fungal stain
Coccidioides	N/A
Blastomyces	N/A
Trichosporon or Rhodotorula	N/A

Hepatosplenic or gastrointestinal

Hepatosplenic or Gastrointestinal
Histoplasma	Serum Histoplasma antigen
Cryptococcus	Blood culture Serum Cryptococcus antigen Tissue biopsy
Candida	(1-3) beta-D-glucan
Coccidioides	N/A
Blastomyces	N/A
Trichosporon or Rhodotorula	N/A

Dermatologic

Dermatologic
Histoplasma	Culture and histology of skin biopsy Serum Histoplasma antigen
Cryptococcus	Culture of purulent material/fluid Serum antigen
Candida	Fungal stain Culture Vaginal pathogens (DNA probe)
Coccidioides	Fungal stain of purulent material CF, ID and ELISA antibodies
Blastomyces	Fungal stain of purulent material CF and ID antibodies, EIA
Trichosporon or Rhodotorula	Culture

Bone

Bone
Histoplasma	Bone marrow culture Serum Histoplasma antigen
Cryptococcus	Bone marrow culture Cryptococcus antigen
Candida	Bone marrow culture (1-3) beta-D-glucan
Coccidioides	Bone marrow culture CF, ID and ELISA antibodies
Blastomyces	Bone marrow culture CF and ID antibodies, EIA
Trichosporon or Rhodotorula	N/A

Genitourinary

Genitourinary
Histoplasma	Urine and serum Histoplasma antigen and CF and ID antibodies Tissue biopsy (focal lesion) Disseminated disease – order fungal blood culture
Cryptococcus	Serum Cryptococcus antigen Tissue biopsy (focal lesion)
Candida	Fungal stain Culture (1-3) beta-D-glucan
Coccidioides	N/A
Blastomyces	Urine culture after prostatic massage CF and ID antibodies, EIA Tissue biopsy (focal lesion)
Trichosporon or Rhodotorula	Urine culture (Trichosporon only)

Tests generally appear in the order most useful for common clinical situations

Test name: Fungal Culture

ARUP #: 0060149

Methodology: Standard reference procedures for fungal culture. Standard reference procedures for identification and/or ITS rDNA Sequencing. DNA probes available for Histoplasma, Coccidioides, and Blastomyces

Use:

Gold standard for diagnosing fungal infection

Limitations:

Notify laboratory if Malassezia furfur is suspected

Test name: Yeast Culture

ARUP #: 0060150

Methodology: Standard reference procedures for yeast culture. Standard reference procedures for identification and/or ITS rDNA Sequencing.

Use:

Gold standard for diagnosing fungi as agent of infection in genital, fecal, and oral specimens

Test name: Fungal Stain, KOH with Calcofluor White

ARUP #: 2004589

Methodology: KOH with Calcofluor White Stain

Use:

Identify fungus from fungal smear (eg, yeast, aseptate hyphae, septate hyphae)

Limitations:

Difficult to classify type of fungus from a smear

Test name: India Ink Stain

ARUP #: 2004593

Methodology: India Ink Stain

Use:

Identify encapsulated yeast (eg, Cryptococcus)

Test name: Blood Culture, Fungal

ARUP #: 0060070

Methodology: BACTEC® Continuous Monitoring System.
Standard reference procedures for identification and/or DNA Sequencing

Use:

Gold standard for diagnosing fungi as agent of infection in blood

Limitations:

Wide range of reported sensitivity for yeast (40-90%)

Test name: Fungal Culture, Skin, Hair or Nails

ARUP #: 0060728

Methodology: Standard reference procedures for fungal culture. Standard reference procedures for identification and/or ITS rDNA Sequencing.

Use:

Gold standard for diagnosing fungi as agent of infection in skin, hair or nails

Test name: Fungal (Mould/Yeast) Identification

ARUP #: 0060163

Methodology: Standard reference procedures for identification, DNA probes and/or ITS rDNA Sequencing

Use:

Identify fungal agent

Test name: Histoplasma Antigen by EIA, Serum

ARUP #: 0092522

Methodology: Semi-quantitative Enzyme Immunoassay

Use:

Diagnose and monitor response to therapy in Histoplasma-caused disease

Limitations:

Rarely positive in chronic cases

Test name: Histoplasma Antigen by EIA, Urine

ARUP #: 0060730

Methodology: Semi-quantitative Enzyme Immunoassay

Use:

Diagnose and monitor response to therapy in Histoplasma-caused disease

Test name: Histoplasma capsulatum Identification by DNA Probe

ARUP #: 0062226

Methodology: Nucleic Acid Probe

Use:

Rapid test for identifying H. capsulatum (yeast or mold form) from pure isolate

Limitations:

Chrysosporium anamorph Nannizziopsis vriesii may cross-react with H. capsulatum AccuProbe^®

Test name: Cryptococcus Antigen, Serum

ARUP #: 0050196

Methodology: Semi-quantitative Enzyme Immunoassay

Use:

Detect antigens of C. neoformans in sera of patients with invasive cryptococcal disease

Test name: Cryptococcus Antigen, CSF

ARUP #: 0050195

Methodology: Semi-quantitative Enzyme Immunoassay

Use:

Detect antigens of C. neoformans in CSF of patients with cryptococcal meningitis

Test name: (1,3)-Beta-D-Glucan (Fungitell®)

ARUP #: 2002434

Methodology: Semi-quantitative Colorimetric Assay

Use:

Detect (1-3) beta-D-glucan in serum samples when a fungal infection is suspected

Aid in diagnosis of invasive Candida infections

Use in conjunction with other diagnostic procedures

Limitations:

Does not detect fungal species that produce very low levels of (1-3) beta-D-glucan (eg, Cryptococcus)

Does not detect zygomycetes (ie, Absidia, Mucor and Rhizopus)

Test name: Vaginal Pathogens DNA Direct Probes

ARUP #: 0065153

Methodology: Qualitative Nucleic Acid Probe

Use:

Detect presence of Candida

Limitations:

Poor specificity; cannot distinguish colonization from active infection

Test name: Coccidioides Antibodies Panel, CSF by CF, ID, ELISA

ARUP #: 0050710

Methodology: Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Detect both IgG and IgM antibodies in acute and convalescent samples
Confirm coccidioidal disease as infectious entity in meningitis

Test name: Coccidioides Antibodies Panel, Serum by CF, ID, ELISA

ARUP #: 0050588

Methodology: Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Detect current or past infection
Use to monitor response to therapy

Limitations:

Negative fungal serology does not rule out possibility of current infection

Test name: Coccidioides immitis Identification by DNA Probe

ARUP #: 0062225

Methodology: Nucleic Acid Probe

Use:

Rapid test for identifying C. immitis (yeast or mold form)

Test name: Blastomyces dermatitidis Identification by DNA Probe

ARUP #: 0062224

Methodology: Nucleic Acid Probe

Use:

Rapid test for identifying B. dermatitidis (yeast or mold form)

Limitations:

Gymmascella hyalinospora, a member of the Ascomycetes order, may cross-react with B. dermatitidis probes

Test name: Blastomyces dermatitidis Antigen EIA

ARUP #: 2002926

Methodology: Quantitative Enzyme Immunoassay

Use:

Useful for diagnosis and monitoring of treatment response

Test name: Blastomyces Antibodies by CF & ID

ARUP #: 0050626

Methodology: Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion

Use:

Detect past or current infection

Additional Tests Available

Test name: Coccidioides Antibodies, IgG & IgM by ELISA

ARUP #: 0050137

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Fungal Antibodies by ID

ARUP #: 0050164

Methodology: Qualitative Immunodiffusion

Comments:

Test name: Fungal Antibodies by CF, Serum

ARUP #: 0050605

Methodology: Semi-Quantitative Complement Fixation

Comments:

Test name: Fungal Identification by ITS rDNA Sequencing

ARUP #: 0060756

Methodology: ITS rDNA Sequencing

Comments:

Identify clinically significant isolates

Test name: Antimicrobial Susceptibility - Yeast Susceptibility

ARUP #: 0060235

Methodology: Broth Microdilution

Comments:

Determine minimum inhibitory antifungal agent concentration to treat identified Candida, Cryptococcus, Geotrichum and Trichosporon species

Agents tested - amphotericin B, anidulafungin, caspofungin, fluconazole, 5-fluorocytosine, itraconazole, micafungin, posaconazole, and voriconazole

Test name: Blastomyces Antibody by CF

ARUP #: 0050130

Methodology: Semi-Quantitative Complement Fixation

Comments:

Use with paired sera taken 3 weeks apart to detect a rise in titer against a single antigen

Test name: Blastomyces Antibody by ID

ARUP #: 0050172

Methodology: Qualitative Immunodiffusion

Comments:

Measure IgG antibodies

Test name: Candida Antibody by ID

ARUP #: 0055565

Methodology: Qualitative Immunodiffusion

Comments:

Exclude systemic candidiasis in immunocompromised patients

Test name: Candida albicans Antibodies, IgA, IgG, & IgM by ELISA

ARUP #: 0095200

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Measure IgG, IgM and IgA antibodies

Antibody testing has limited utility in immunocompromised patients

Best evidence for infection is significant change on two appropriately timed specimens where both tests are done in the same laboratory at the same time; however, low levels of IgM may occasionally persist for >12 months

Test name: Coccidioides Antibody by CF

ARUP #: 0050170

Methodology: Semi-Quantitative Complement Fixation

Comments:

Detect current or past infection

Monitor response to therapy

Least sensitive in pulmonary cavitary disease

Test name: Coccidioides Antibody by ID

ARUP #: 0050183

Methodology: Qualitative Immunodiffusion

Comments:

Detect current or past infection

Monitor response to therapy

Test name: Coccidioides Antibody, IgG by ELISA

ARUP #: 0050179

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Detect current or past infection

Negative fungal serology does not rule out possibility of current infection

Test name: Coccidioides Antibody, IgM by ELISA

ARUP #: 0050178

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Detect current or past infection

Negative fungal serology does not rule out possibility of current infection

For equivocal results, repeat test in 10-14 days

Test name: Cryptococcus Antibody

ARUP #: 0098947

Methodology: Immunofluorescence Assay

Comments:

Detect antibodies to Cryptococcus

Test name: Histoplasma Antibodies by CF

ARUP #: 0050625

Methodology: Semi-Quantitative Complement Fixation

Comments:

Detect current or past Histoplasma infection

Test name: Histoplasma Antibodies by CF & ID

ARUP #: 0050627

Methodology: Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion

Comments:

Detect current or past Histoplasma infection

Negative fungal serology does not rule out possibility of current infection

Test name: Histoplasma Antibody by ID

ARUP #: 0050174

Methodology: Qualitative Immunodiffusion

Comments:

Identify Histoplasma as causative agent in disease

Negative fungal serology does not rule out possibility of current infection

Test name: Fungal Antibodies by CF, CSF

ARUP #: 0050750

Methodology: Semi-Quantitative Complement Fixation

Comments:

Test name: Yeast Differentiation by PNA FISH

ARUP #: 2004769

Methodology: Qualitative Peptide Nucleic Acid Fluorescence in situ Hybridization (PNA FISH)

Comments:

Presumptive result; definitive identification made from subculture

Guidelines

General

ARUP Institute for Clinical and Experimental Pathology®

Comprehensive Review: June 2010
Last Update: June 2010

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