Mold-Associated Infections

Diagnosis

Criteria for Diagnosis

  • Primary diagnostic criteria for allergic bronchopulmonary aspergillosis (IDSA, 2008)
    • Asthma
    • Peripheral eosinophilia
    • Immediate scratch test reactivity to Aspergillus antigen
    • Precipitating antibodies to Aspergillus antigen
    • Elevated serum IgE concentrations
    • History of pulmonary infiltrates (transient or fixed)
    • Central bronchiectasis

Diagnosis of Mold-Associated Syndromes

  • Pneumonia
    Pneumonia
    OrganismRecommended Testing
    Hyaline molds
    • Bronchoalveolar lavage (BAL) with fungal stain and culture (A [Aspergillus fumigatus], F [Fusarium spp], S [Scedosporium spp])
    • Biopsy with fungal culture of tissue
    • Galactomannan (A) on BAL and serum
    • (1,3)-β-D-glucan (A, F, possibly S)
    Zygomycetes
    • Biopsy tissue culture
    Dematiaceous fungi
    • BAL
    • Biopsy tissue culture
    Hypersensitivity
    Hypersensitivity
    OrganismRecommended Testing
    Hyaline molds
    • Aspergillus fumigatus scratch test (A)
    • Serum IgE (A)
    • Aspergillus antibodies CF, ID (A)
    • Chest x-ray/CT scan (A)
    • Fungal balls – sputum culture + Aspergillus antibodies CF, ID (A)
    Zygomycetes
    • N/A
    Dematiaceous fungi
    • N/A
    Ophthalmic
    Ophthalmic
    OrganismRecommended Testing
    Hyaline molds
    • Culture (A, F, S)
    Zygomycetes
    • Culture
    Dematiaceous fungi
    • Culture
    Otorhinolaryngologic
    Otorhinolaryngologic
    OrganismRecommended Testing Based on Criteria
    Hyaline molds
    • Ball of hyphae with obstruction
      • CT scan/MRI and culture (A, F, S)
    • Acute invasive rhinosinusitis – associated with invasive disease
      • CT scan/MRI and fungal culture of tissue (A, F, S)
    Zygomycetes
    • Fungal culture of tissue
    Dematiaceous fungi
    • Allergic – CT scan/MRI with lack of invasion
    • Acute invasion – CT scan/MRI and fungal culture of tissue
    Central nervous system
    Central Nervous System
    OrganismRecommended Testing
    Hyaline molds
    • Cerebrospinal fluid – stain and culture (A, F, S)
    Zygomycetes
    • Fungal culture of tissue
    Dematiaceous fungi
    • Fungal culture
    Cardiac/mediastinum
    Cardiac/Mediastinum
    OrganismRecommended Testing
    Hyaline molds
    • Blood culture (A, F, S)
    • Galactomannan antigen (A)
    • (1,3)-β-D-glucan (A, F, possibly S)
    Zygomycetes
    • Blood culture (rarely positive A or S)
    Dematiaceous fungi
    • N/A
    Hepatosplenic or gastrointestinal (GI) system
    Hepatosplenic or Gastrointestinal (GI) System
    OrganismRecommended Testing
    Hyaline molds
    • N/A
    Zygomycetes
    • Fungal culture of tissue
    Dematiaceous fungi
    • N/A
    Dermatologic
    Dermatologic
    OrganismRecommended Testing
    Hyaline molds
    • Fungal stain and culture of pus (A, F, S)
    Zygomycetes
    • Fungal stain and culture
    Dematiaceous fungi
    • Fungal stain and culture
    Bone
    Bone
    OrganismRecommended Testing
    Hyaline molds
    • Bone marrow culture (A, F, S)
    Zygomycetes
    • Bone marrow culture
    Dematiaceous fungi
    • Mycetoma – stain of pus
    Disseminated/invasive
    Disseminated/Invasive
    OrganismRecommended Testing
    Hyaline molds
    • Blood culture (A, F, S)
    • Galactomannan antigen (A)
    Zygomycetes
    • Blood culture
    Dematiaceous fungi
    • N/A

Differential Diagnosis

Monitoring

  • Galactomannan antigen
    • May be used to monitor immunocompromised patients who are experiencing neutropenia
      • Limited sensitivity in non-neutropenic patients
    • Requires a moderate prevalence of invasive aspergillosis in the community; not as useful for monitoring if prevalence is low
  •  (1,3)-β-D-glucan (Fungitell)
    • May be used to monitor immunocompromised patients who are experiencing neutropenia; most experience is with monitoring for invasive aspergillosis and candidiasis
    • Test has high negative predictive value; false negatives uncommon

Clinical Background

Mold infections range in spectrum from colonization to hypersensitivity reactions. In addition, opportunistic molds have become increasingly recognized as a cause of life-threatening invasive infection in severely ill or immunocompromised patients.

Epidemiology

  • Invasive fungal disease occurs most commonly in immunocompromised patients

Etiology

  • Molds most often associated with significant disease include the following
    • Hyaline molds (three most common)
      • Aspergillus fumigatus (A)
      • Fusarium spp (F)
      • Scedosporium spp (S)
    • Zygomycetes
      • Hallmarks of Zygomycetes infection are vascular invasion and tissue necrosis (presence of black tissue)
    • Dematiaceous fungi
      • Includes a large group of darkly pigmented organisms

Risk Factors

  • At risk for infection
    At Risk for Infection
    OrganismRisk Group
    Hyaline molds
    Zygomycetes
    Dematiaceous fungi
    • All immunocompromised

Mold-associated Signs and Symptoms – Pulmonary

  • Pneumonia
    Pneumonia
    OrganismDisease/Syndrome
    Hyaline molds
    Zygomycetes
    • Infiltrate or cavity on x-ray
    • Hemoptysis
    • Necrotizing pneumonias
    • Mycotic pulmonary aneurysms
    Dematiaceous fungi
    • Rare pulmonary dematiaceous disease
    Hypersensitivity
    Hypersensitivity
    OrganismDisease/Syndrome
    Hyaline molds
    • Endobronchial Scedosporium and Aspergillus – fungal balls (A, S)
    • Allergic bronchopulmonary aspergillosis and Scedosporium pneumonia (A, S)
    • Asthma (A)
    Zygomycetes
    • N/A
    Dematiaceous fungi
    • N/A

Mold-associated Signs and Symptoms – Sites Other than Pulmonary

  • Ophthalmic
    Ophthalmic
    OrganismDisease/Syndrome
    Hyaline molds
    • Endophthalmitis (A, S)
    • Keratitis (A, F)
    Zygomycetes
    • Orbital invasion from sinus
    Dematiaceous fungi
    • Keratitis
    Otorhinolaryngologic
    Otorhinolaryngologic
    OrganismDisease/Syndrome
    Hyaline molds
    • Otomycosis – growth on cerumen, detritus in ear canal (A, F, S)
    • Sinus (A, F, S)
      • Ball of hyphae with obstruction
      • Acute invasive rhinosinusitis
      • Chronic fibrosing granulomatous inflammation with tissue invasion
    Zygomycetes
    • Orbital cellulitis
    • Cranial nerve palsies
    • Cavernous sinus and internal artery thromboses
    • Invasive rhinosinusitis
    Dematiaceous fungi
    • Allergic fungal sinusitis
    • Acute invasive rhinosinusitis
    Central nervous system
    Central Nervous System
    OrganismDisease/Syndrome
    Hyaline molds
    • Brain abscess (A, F, S)
    • Meningitis – rare (A, F, S)
    • Vascular infarcts in brain (A)
    Zygomycetes
    • Brain abscesses – generally invasive from sinuses
    • Meningitis – rare
    Dematiaceous fungi

    Rare CNS dissemination, brain abscesses, meningitis

    Cardiac/mediastinum
    Cardiac/Mediastinum
    OrganismDisease/Syndrome
    Hyaline molds
    Zygomycetes
    • Endocarditis
    Dematiaceous fungi

    N/A

    Hepatosplenic or gastrointestinal (GI) system
    Hepatosplenic or Gastrointestinal (GI) System
    OrganismDisease/Syndrome
    Hyaline molds
    • Peritonitis – rare (S)
    Zygomycetes
    • Ulcers – all portions of GI tract 
      • Stomach most commonly affected
    Dematiaceous fungi
    • N/A
    Dermatologic
    Dermatologic
    OrganismDisease/Syndrome
    Hyaline molds
    • Onychomycosis (A, F, S)
    • Invasion of catheters (A, F)
    • Burns (A)
    • Necrotic skin lesions (S)
    • Papules, nodules (tender) (F)
    Zygomycetes
    • Ulcers
    • Necrosis
    Dematiaceous fungi
    • Blastomycosis nodules that become verrucous lesions and plaques
    • Mycetoma – usually lower extremity; single red nodule 
      •  Draining sinus tract, extrusion of granules
    • Chronic dematiaceous fungi – may lead to squamous cell carcinoma
    Bone
    Bone
    OrganismDisease/Syndrome
    Hyaline molds
     
    • Vertebral (A most common, S)
    • Long bones and joints (S)
    Zygomycetes
    Dematiaceous fungi
    • N/A

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Aspergillus Antibodies by CF and ID 0050101
Method: Semi-Quantitative Complement Fixation/Qualitative Immunodiffusion

Test for Aspergillus as cause of pulmonary disease

   
Allergen, Fungi and Molds, Aspergillus fumigatus 0055061
Method: Quantitative ImmunoCAP Fluorescent Enzyme Immunoassay

Test for Aspergillus as cause of pulmonary disease

   
Aspergillus Galactomannan Antigen by EIA, Serum 0060068
Method: Semi-quantitative Enzyme Immunoassay
Diagnose invasive/disseminated aspergillosis

Negative results do not rule out invasive aspergillosis

Many agents may cross-react with test (food, antibiotics, etc)

Recommend serial sampling for high-risk patients if suspicion is high

Single positive test result (index ≥0.5) should be confirmed by separate serum specimen

Aspergillus Galactomannan Antigen by EIA, Bronchoscopy 2003150
Method: Semi-quantitative Enzyme Immunoassay

Diagnose invasive/disseminated aspergillosis

   
Fungal Culture 0060149
Method: Culture/Identification

Gold standard test for diagnosing fungi as agent of infection in pus, sputum, tissue, or urine

   
Fungal Culture, Skin, Hair or Nails 0060728
Method: Culture/Identification

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

   
Fungal Stain, KOH with Calcofluor White 2004589
Method: Microscopy

Identify fungus from fungal smear

Difficult to identify type of fungus from a smear

 
Fungal (Mold/Yeast) Identification 0060163
Method: Identification. Methods may include biochemical, mass spectrometry, or sequencing.

Identify fungal agent

Testing to differentiate between Candida albicans and C. dubliniensis performed by request only  
Blood Culture, Fungal 0060070
Method: Continuous Monitoring Blood Culture/Identification

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

Poor sensitivity for Aspergillus spp, Zygomycetes, and dematiaceous fungi

 
Aspergillus fumigatus Antibody, IgG by ELISA 0097771
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Diagnose antibody response to A. fumigatus

   
(1,3)-Beta-D-Glucan (Fungitell) 2002434
Method: Semi-Quantitative Colorimetry
Diagnose invasive/disseminated fungal infection

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

Does not detect Zygomycetes spp, which are not known to produce (1,3)-β-D-glucan (eg, Absidia, Mucor, Rhizopus)

 
Antimicrobial Susceptibility - Fungal (Yeasts and Molds) 2009257
Method: Broth Microdilution

Test for level of antifungal agent required for treatment of identified mold spp

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

Selective reporting by organism

Assay does not test for environmental molds

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Fungal Antibodies by Immunodiffusion 0050164
Method: Qualitative Immunodiffusion
Aspergillus Antibody by CF 0050100
Method: Semi-Quantitative Complement Fixation

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

Aspergillus spp. Antibodies by Immunodiffusion 0050171
Method: Qualitative Immunodiffusion

Use to measure IgG and precipitins

Fungal Antibodies by CF, CSF 0050750
Method: Semi-Quantitative Complement Fixation
Fungal Antibodies by CF, Serum 0050605
Method: Semi-Quantitative Complement Fixation
Candida albicans Antibodies IgA, IgG, and IgM by ELISA (Temporary Referral as of 09/11/14) 0095200
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

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

Histoplasma capsulatum Identification by DNA Probe 0062226
Method: Nucleic Acid Probe
Coccidioides immitis Identification by DNA Probe 0062225
Method: Nucleic Acid Probe
Blastomyces dermatitidis Identification by DNA Probe 0062224
Method: Nucleic Acid Probe
Fungal Identification by ITS rDNA Sequencing 0060756
Method: Sequencing