Yeast-Associated Syndromes

Clinical Background

Yeasts are capable of causing 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 that most likely cause disease include:
- Yeasts - Cryptococcus neoformans, Candida spp
  - Emerging infectious yeasts 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 Pulmonary Signs and Symptoms
	Histoplasma	Cryptococcus	Candida	Coccidioides	Blastomyces	Trichosporon Rhodotorula
Risk factors for severe pneumonia and disseminated disease	Young children HIV Organ transplatation	Sarcoidosis Diabetes mellitus HIV	N/A	Pregnancy Heritage - Filipino - Native American - African American	N/A	Severely ill patients (eg, leukemia)
Acute primary pulmonary infection	Clinical picture similar to tuberculosis with fever, weight loss and lymphadenopathy	Fever Chest pain Cough Sputum Weight loss	NA	Clinical picture similar to tuberculosis with fever, weight loss and lymphadenopathy	Clinical picture similar to influenza	N/A
Chronic pulmonary disease	Calcified nodes Chronic cavitary disease Mediastinal granuloma Fibrosis	N/A	N/A	Coin lesions (coccidiomas) Cavitary disease (thin walled) Granulomas	Chronic granulomatous disease (Gilchrist disease)	N/A

Yeast-Associated Signs and Symptoms - Sites Other Than Pulmonary
	Histoplasma	Cryptococcus	Candida	Coccidioides	Blastomyces	T-Trichosporon or R-Rhodotorula
Ophthalmologic	Uveitis and panophthalmitis Presumed ocular histoplasmosis syndrome (POHS) consists of posterior uveitis with choroidal scars and neovascularization and loss of central vision	Ocular palsies Papilledema Keratitis Endophthalmitis	Fungal keratitis Endophthalmitis	N/A	N/A	N/A
Otorhinolaryngologic	N/A	Gingivitis Sinusitis Salivary gland enlargement	Thrush Nasal ulcers Otitis externa	N/A	N/A	N/A
Central nervous system	Chronic meningitis Cerebritis and mass lesion	Meningitis Intracranial abscesses Spinal granuloma	Meningitis Diffuse microabscesses in the brain	Chronic meningitis with indolent course	Abscesses Meningitis	N/A
Hepatosplenic or gastrointestinal	Hepatosplenomegaly Chronic granulomatous hepatitis	Disseminated yeast infections (hepatitis, peritonitis, nodular or ulcerated lesions of the colon)	Disseminated yeast infections (esophagitis, gastrointestinal ulcers, peritonitis, hepatic and splenic abscesses)	N/A	N/A	N/A
Dermatologic	Discrete erythematous skin papules in HIV patients	Papules Subcutaneous abscesses Purpura Bullae Ulcers Draining sinuses	Folliculitis, generalized cutaneous form, disseminated skin infections, intertrigo, paronychia, onychomycosis, diaper rash, vaginitis, chronic mucocutaneous candidiasis	Maculopapular to verrucous lesions Subcutaneous abscesses Reactive eruptions (contain no organisms) Includes: Erythema Nodosum Erythema multiforme Toxic erythema Sweet syndrome	Verrucous or ulcerative lesions Subcutaneous nodules	Red papular lesions (T) Catheter-related fungemia (R)
Bone	Osteomyelitis	Osteolytic lesions with soft tissue abscesses	Osteomyelitis most common in spine, wrist, femur, ribs, scapula and proximal humerus Arthritis	Osteomyelitis most common in knees, hands, vertebrae and long bones Symmetric arthritis referred to as desert rheumatism	Osteomyelitis most common in long bones, vertebrae and ribs	N/A
Genitourinary	Epididymitis Testicular and prostatic abscesses (rarely symptomatic)	Prostatitis Renal abscesses Genital lesions	Vulvovaginitis Balanitis Papillary necrosis Fungus ball Perinephric abscess	N/A	Prostatitis Epididymitis	Hematuria (T) Funguria (T)

See Also

Mold-Associated Syndromes

Diagnosis

Indications for testing

At-risk patient with suspected disease

Yeast-Associated Syndromes - Diagnosis
	Histoplasma	Cryptococcus	Candida	Coccidioides	Blastomyces	Trichosporon or Rhodoturula
Respiratory --Acute primary infection	Sputum fungal stain Histoplasma EIA serum and/or urine Tissue culture	Fungal stain Serum Cryptococcus antigen Culture	Tissue biopsy specimen showing invasion Tissue culture	Sputum fungal stain Tissue culture Serum ID	Sputum fungal stain Serum ID, CF Tissue culture	NA
Respiratory --Chronic pulmonary disease	EIA serum or urine Tissue culture Antibody detection	CF antibodies	NA	NA	Serum CF, ID	NA
Central Nervous System	Cerebral spinal fluid (CSF) stain and culture Serum Histoplasma antigen	India ink Serum Cryptococcus antigen CSF Cryptococcus antigen Culture	Culture Fungal stain (1-3) Beta-D glucan	CSF stain and culture CF, ID and ELISA antibodies	CSF stain and culture CF and ID antibodies	NA
Ophthalmologic	Culture Serum Histoplasma antigen and antibody	Culture Serum Cryptococcus antigen	Culture (vitreous fluid) Blood culture (1-3) Beta-D glucan	NA	NA	NA
Otorhinolaryngologic	N/A	Fungal stain Serum Cryptococcus antigen Culture	Culture Fungal stain	NA	NA	NA
Hepatosplenic or gastrointestinal	Serum Histoplasma antigen	Blood culture Serum Cryptococcus antigen Tissue biopsy	Candida mannan (latex agglutination) (1-3) Beta-D glucan	NA	NA	NA
Dermatologic	Culture and histology of skin biopsy Serum Histoplasma antigen	Culture of purulent material/fluid Serum antigen	Fungal stain Culture Candida mannan Vaginal pathogens (DNA probe)	Fungal stain of purulent material CF, ID and ELISA antibodies	Fungal stain of purulent material CF and ID antibodies	Culture
Bone	Bone marrow culture Serum Histoplasma antigen	Bone marrow culture Cryptococcal antigen	Bone marrow culture Candida mannan 1-3) Beta-D glucan	Bone marrow culture CF, ID and ELISA antibodies	Bone marrow culture CF and ID antibodies	NA
Genitourinary	Urine and serum Histoplasma antigen and CF and ID antibodies Tissue biopsy (focal lesion) Disseminated disease, order fungal blood culture	Serum Cryptococcus antigen Tissue biopsy (focal lesion)	Fungal stain Culture Candida mannan (1-3) Beta-D glucan	NA	Urine culture after prostatic massage CF and ID antibodies Tissue biopsy (focal lesion)	Urine culture (Trichosporon only)

Tests

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 and identification of mould/yeast. DNA probes available for Histoplasma, Coccidioides, and Blastomyces

Use:

Gold standard test for diagnosing fungal infection

Limitations:

Notify laboratory if Malassezia furfur is suspected

Follow-up:

Test name: Yeast Culture

ARUP #: 0060150

Methodology: Standard reference procedures for culture and identification, and ITS rDNA Sequencing for select isolates.

Use:

Gold standard test for diagnosing yeast infection

Test name: Fungal Stain - KOH with Calcofluor White

ARUP #: 0060161

Methodology: KOH with Calcofluor White/Microscopic Exam

Use:

Identify fungus from fungal smear (e.g., yeast, aseptate hyphae, septate hyphae)

Limitations:

Difficult to classify type of fungus from a smear

Follow-up:

Test name: India Ink Exam

ARUP #: 0060146

Methodology: India Ink Microscopic Exam

Use:

Identify encapsulated yeast (e.g., Cryptococcus)

Limitations:

Follow-up:

Test name: Blood Culture, Fungal

ARUP #: 0060070

Methodology: Bactec® 9240, continuous monitoring systems. Standard reference procedures for identification of positive cultures.

Use:

Gold standard test for diagnosing fungi as agent of infection in blood

Limitations:

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

Follow-up:

Test name: Fungal Culture, Skin, Hair or Nails

ARUP #: 0060728

Methodology: Standard reference procedures for fungal culture and identification of mould/yeast.

Use:

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

Limitations:

Follow-up:

Test name: Histoplasma Blood Culture

ARUP #: 0060145

Methodology: Lysis Centrifugation (Isolator™)/DNA probes available for identification

Use:

Determine presence of Histoplasma in blood

Limitations:

Sensitivity variable

Follow-up:

Test name: Fungal (Mould) Identification

ARUP #: 0060163

Methodology: Standard reference procedures for mould identification

Use:

Identify fungal agent

Limitations:

Follow-up:

Test name: Histoplasma Antigen, Serum

ARUP #: 0092522

Methodology: Enzyme Immunoassay

Use:

Diagnose and monitor response to therapy in Histoplasma-caused disease

Limitations:

Rarely positive in chronic cases

Follow-up:

Test name: Histoplasma Antigen by EIA, Urine

ARUP #: 0060730

Methodology: Enzyme Immunoassay

Use:

Diagnose and monitor response to therapy in Histoplasma-caused disease

Limitations:

Follow-up:

Test name: Histoplasma capsulatum Identification by DNA Probe

ARUP #: 0062226

Methodology: Nucleic Acid Probe

Use:

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

Limitations:

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

Test name: Cryptococcus Antigen, Serum

ARUP #: 0050196

Methodology: Enzyme Immunoassay

Use:

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

Limitations:

Follow-up:

Test name: Cryptococcus Antigen, CSF

ARUP #: 0050195

Methodology: Enzyme Immunoassay

Use:

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

Limitations:

Follow-up:

Test name: Candida Antigen

ARUP #: 0060098

Methodology: Latex Agglutination

Use:

Tool to diagnose invasive disease

Limitations:

Follow-up:

Test name: (1-3) Beta-D Glucan Assay

ARUP #:

Methodology:

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 which produce very low levels of (1-3) Beta-D glucan (e.g., Cryptococcus)

Does not detect Zygomycetes (i.e., Absidia, Mucor and Rhizopus)

Test name: Vaginal Pathogens DNA Direct Probes

ARUP #: 0065153

Methodology: Nucleic Acid Probe

Use:

Detect presence of Candida

Limitations:

Poor specificity; cannot distinguish colonization from active infection

Follow-up:

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

ARUP #: 0050710

Methodology: Complement Fixation/Immunodiffusion/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: Complement Fixation/Immunodiffusion/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 mould form)

Limitations:

Follow-up:

Test name: Blastomyces Antibodies by CF & ID

ARUP #: 0050626

Methodology: Complement Fixation/Immunodiffusion

Use:

Detect past or current infection

Limitations:

Follow-up:

Test name: Blastomyces dermatitidis Identification by DNA Probe

ARUP #: 0062224

Methodology: Nucleic Acid Probe

Use:

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

Limitations:

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

Follow-up:

Additional Tests Available

Test name: Coccidioides Antibodies, IgG & IgM by ELISA

ARUP #: 0050137

Methodology: Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Fungal Antibodies by ID

ARUP #: 0050164

Methodology: Immunodiffusion

Comments:

Test name: Fungal Antibodies by CF, Serum

ARUP #: 0050605

Methodology: Complement Fixation

Comments:

Test name: Yeast Identification

ARUP #: 0063998

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

Comments: Identify clinically significant isolates

Test name: Yeast 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 concentration of Candida spp

Test name: Blastomyces Antibody by CF

ARUP #: 0050130

Methodology: 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: Immunodiffusion

Comments: Use to measure IgG antibodies

Test name: Candida Antibody by ID

ARUP #: 0055565

Methodology: Immunodiffusion

Comments: Exclude systemic candidiasis in immunocompromised patients

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

ARUP #: 0095200

Methodology: Enzyme-Linked Immunosorbent Assay

Comments: Use to measure IgG, IgM and IgA antibodies

Test name: Coccidioides Antibody by CF

ARUP #: 0050170

Methodology: Complement Fixation

Comments: Detect current or past infectionUse to monitor response to therapyLeast sensitive in pulmonary cavitary disease

Test name: Coccidioides Antibody by ID

ARUP #: 0050183

Methodology: Immunodiffusion

Comments: Detect current or past infectionUse to monitor response to therapy

Test name: Coccidioides Antibody, IgG by ELISA

ARUP #: 0050179

Methodology: Enzyme-Linked Immunosorbent Assay

Comments: Detect current or past infectionNegative fungal serology does not rule out possibility of current infection

Test name: Coccidioides Antibody, IgM by ELISA

ARUP #: 0050178

Methodology: Enzyme-Linked Immunosorbent Assay

Comments: Detect current or past infectionNegative fungal serology does not rule out possibility of current infectionFor equivocal results repeat testing in 10-14 days may be helpful

Test name: Cryptococcus Antibody

ARUP #: 0098947

Methodology: Immunofluorescence Assay

Comments: Detect antibodies to Cryptococcus

Test name: Histoplasma Antibodies by CF

ARUP #: 0050625

Methodology: Complement Fixation

Comments: Detect current or past Histoplasma infection

Test name: Histoplasma Antibodies by CF & ID

ARUP #: 0050627

Methodology: Complement Fixation/Immunodiffusion

Comments: Detect current or past Histoplasma infectionNegative fungal serology does not rule out possibility of current infection

Test name: Histoplasma Antibody by ID

ARUP #: 0050174

Methodology: Immunodiffusion

Comments: Identify Histoplasma as causative agent in diseaseNegative fungal serology does not rule out possibility of current infection

Test name: Antimicrobial Susceptibility - Mould Susceptibility

ARUP #: 0060227

Methodology: Broth Microdilution

Comments:

Test name: Fungal Antibodies by CF, CSF

ARUP #: 0050750

Methodology: Complement Fixation

Comments:

References

General References

Bialek R, Gonzalez GM, Begerow D, Zelck UE. Coccidioidomycosis and blastomycosis: advances in molecular diagnosis. FEMS Immunol Med Microbiol. 2005;45(3):355-360.

Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am. 2003;17(1):21-40, vii.

Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006;20(3):507-5vi.

DiCaudo DJ. Coccidioidomycosis: a review and update. J Am Acad Dermatol. 2006;55(6):929-942.

Ellepola AN, Morrison CJ. Laboratory diagnosis of invasive candidiasis. J Microbiol. 2005;43 Spec No:65-84.

Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20(1):115-132.

Perfect JR. Cryptococcus neoformans: the yeast that likes it hot. FEMS Yeast Res. 2006;6(4):463-468.

Perlroth J, Choi B, Spellberg B. Nosocomial fungal infections: epidemiology, diagnosis, and treatment. Med Mycol. 2007;45(4):321-346.

Saubolle MA. Laboratory aspects in the diagnosis of coccidioidomycosis. Ann N Y Acad Sci. 2007;1111:301-314.

Tuon FF, de Almeida GM, Costa SF. Central venous catheter-associated fungemia due to Rhodotorula spp. --a systematic review. Med Mycol. 2007;45(5):441-447.

Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther. 2006;6(11):1207-1221.

Yu MK, Rodgers GM. Immune-mediated thrombocytopenia associated with valley fever. Am J Hematol. 2002;70(1):81-82.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

Cloud JL, Bauman SK, Neary BP, Ludwig KG, Ashwood ER. Performance characteristics of a polyclonal enzyme immunoassay for the quantitation of Histoplasma antigen in human urine samples. Am J Clin Pathol. 2007;128(1):18-22.

Cloud JL, Bauman SK, Pelfrey JM, Ashwood ER. Biased report on the IMMY ALPHA Histoplasma antigen enzyme immunoassay for diagnosis of histoplasmosis. Clin Vaccine Immunol. 2007;14(10):1389-1390.

Erali M, Pounder JI, Woods GL, Petti CA, Wittwer CT. Multiplex single-color PCR with amplicon melting analysis for identification of Aspergillus species. Clin Chem. 2006;52(7):1443-1445.

Yu MK, Rodgers GM. Immune-mediated thrombocytopenia associated with valley fever. Am J Hematol. 2002;70(1):81-82.

Medical Reviewers

Carney, Heather, M.D. Assistant Medical Director, Transfusion Services at ARUP Laboratories; Pathology, University of Utah

Litwin, Christine, M.D. Medical Director, Immunology at ARUP Laboratories; Professor, Clinical Pathology, University of Utah

Petti, Cathy A., M.D. Medical Director, Infectious Diseases at ARUP Laboratories; Assistant Professor, Pathology and Medicine, University of Utah

Comprehensive Review: May 2008
Last Update: September 2008