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
  Organism	Recommended 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
  Organism	Recommended 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
  Organism	Recommended Testing
  Hyaline molds	Culture (A, F, S)
  Zygomycetes	Culture
  Dematiaceous fungi	Culture

  Otorhinolaryngologic

  Otorhinolaryngologic
  Organism	Recommended 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
  Organism	Recommended Testing
  Hyaline molds	Cerebrospinal fluid – stain and culture (A, F, S)
  Zygomycetes	Fungal culture of tissue
  Dematiaceous fungi	Fungal culture

  Cardiac/mediastinum

  Cardiac/Mediastinum
  Organism	Recommended 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
  Organism	Recommended Testing
  Hyaline molds	N/A
  Zygomycetes	Fungal culture of tissue
  Dematiaceous fungi	N/A

  Dermatologic

  Dermatologic
  Organism	Recommended 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
  Organism	Recommended Testing
  Hyaline molds	Bone marrow culture (A, F, S)
  Zygomycetes	Bone marrow culture
  Dematiaceous fungi	Mycetoma – stain of pus

  Disseminated/invasive

  Disseminated/Invasive
  Organism	Recommended Testing
  Hyaline molds	Blood culture (A, F, S) Galactomannan antigen (A)
  Zygomycetes	Blood culture
  Dematiaceous fungi	N/A

Differential Diagnosis

• Pulmonary
  • Community-acquired pneumonia
  • M. tuberculosis
  • Malignancy
  • Bronchiectasis
  • Idiopathic fibrosis
  • Cystic fibrosis
• Central nervous system
  • Meningitis (bacterial, viral)
  • Malignant metastasis
  • M. tuberculosis
• Dermatologic
  • M. leprae
  • Sporothrix schenckii (sporotrichosis)
  • M. tuberculosis
  • Sarcoidosis
  • Cutaneous granuloma
  • Squamous cell carcinoma
  • Leishmania spp (leishmaniasis)
• Ophthalmic
  • Bacterial keratitis
  • Uveitis
• Bone
  • Osteomyelitis (bacterial)
  • Malignancy
    • Children – Ewing sarcoma
    • Adults – metastatic disease, primary bone tumor

Monitoring

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
  Organism	Risk Group
  Hyaline molds	All immunocompromised  Special risk   Acute leukemia (ALL, AML) Organ transplant Prolonged neutropenia
  Zygomycetes	All immunocompromised  Special risk  Organ transplant  Diabetes, renal insufficiency Acidosis risk Hemochromatosis medication (deferoxamine)
  Dematiaceous fungi	All immunocompromised

Mold-associated Signs and Symptoms – Pulmonary

• Pneumonia

  Pneumonia
  Organism	Disease/Syndrome
  Hyaline molds	Acute respiratory distress syndrome Chronic inflammatory process in colonized cystic fibrosis patients (A, S) Necrotizing pneumonias – halo, crescent signs (A) Pulmonary mycetoma (S) Rapidly progressive consolidation Tracheobronchitis in lung transplantation (A, S)
  Zygomycetes	Infiltrate or cavity on x-ray Hemoptysis Necrotizing pneumonias Mycotic pulmonary aneurysms
  Dematiaceous fungi	Rare pulmonary dematiaceous disease

  Hypersensitivity

  Hypersensitivity
  Organism	Disease/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
  Organism	Disease/Syndrome
  Hyaline molds	Endophthalmitis (A, S) Keratitis (A, F)
  Zygomycetes	Orbital invasion from sinus
  Dematiaceous fungi	Keratitis

  Otorhinolaryngologic

  Otorhinolaryngologic
  Organism	Disease/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
  Organism	Disease/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
  Organism	Disease/Syndrome
  Hyaline molds	Endocarditis (A, F, S) Pericarditis (A, F, S)
  Zygomycetes	Endocarditis
  Dematiaceous fungi	N/A

  Hepatosplenic or gastrointestinal (GI) system

  Hepatosplenic or Gastrointestinal (GI) System
  Organism	Disease/Syndrome
  Hyaline molds	Peritonitis – rare (S)
  Zygomycetes	Ulcers – all portions of GI tract  Stomach most commonly affected
  Dematiaceous fungi	N/A

  Dermatologic

  Dermatologic
  Organism	Disease/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
  Organism	Disease/Syndrome
  Hyaline molds	Vertebral (A most common, S) Long bones and joints (S)
  Zygomycetes	Rare bone necrosis
  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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Fungal Antibodies by ID 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 Antibody by ID 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 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