Basics
Description
- Diseases caused by species of the mold Aspergillus include superficial, immune-mediated, and invasive conditions depending on host factors.
- Most human disease is caused by Aspergillus fumigatus, Aspergillus flavus, or Aspergillus niger; other Aspergillus spp. may occasionally cause disease.
Epidemiology
- Aspergillus spp. are common, ubiquitous environmental saprophytic molds that are found growing in soil, grain, dung, bird droppings, and decaying plant matter.
- Reproduce through conidia (spore) formation. Spores are hardy and become airborne when soil is disturbed.
- Conidia are inhaled and are typically eliminated by alveolar macrophages and neutrophils.
- Disease occurs when airborne spores are inhaled but not effectively cleared; person-to-person spread does not occur.
- The incubation period has not been defined.
- Nosocomial infections can occur when ventilation or water systems become contaminated or when large numbers of spores become airborne during nearby construction or renovation projects.
Incidence
Aspergillosis incidence varies by the population studied. It is not common in a normal host. Ten percent of patients needing sinus surgery have Aspergillus. Up to 5% of leukemia and bone marrow transplant patients may develop invasive aspergillosis.
Risk Factors
- Otomycosis, fungal sinusitis, and allergic bronchopulmonary aspergillosis (ABPA) can occur in otherwise healthy patients.
- Most patients infected with Aspergillus have some degree of immunocompromise.
- Patients receiving chemotherapy for malignancy or rheumatologic disorders, chronic steroid therapy, organ and bone marrow transplant recipients, and those with HIV or primary immunodeficiencies are at increased risk.
General Prevention
- Hospitalized, immunosuppressed patients are at risk for invasive aspergillosis.
- Careful control of airflow using filters and laminar flow systems especially aimed at limiting exposure to air from construction sites is important.
- Shower heads should be cleaned regularly to prevent aerosolization of mold particles.
Pathophysiology
- Aspergillus most frequently enters the body through the respiratory tract; however, the ear canal and breaks in the skin (especially if acquired from contact with a soiled surface) can also allow infection to occur.
- Progression to disease depends largely on its ability to evade host defenses.
- Macrophages and neutrophils can typically eliminate Aspergillus without difficulty, explaining its rarity in normal hosts.
- Aspergillus produces proteolytic enzymes and cytotoxins, which may contribute to its pathogenesis.
- Conditions that alter the normal immunologic mechanisms predispose to invasive aspergillosis. Examples include leukemia (neutropenia), corticosteroids (decreased neutrophil mobilization and macrophage killing), and chronic granulomatous disease (decreased oxidative-mediated killing).
Etiology
Aspergillus sp.: A. fumigatus is most common and can cause the whole spectrum of disease. A. niger causes sinus and otomycosis and A. flavus causes sinus disease.
Commonly Associated Conditions
- Cutaneous: typically follows trauma, can also occur in premature infants or due to embolism in disseminated disease
- Otomycosis: typically a localized infection, often a superinfection of bacterial otitis externa. More common in warm, moist climates. Host may be normal or have altered mucosal immunity (diabetes, eczema, steroid use).
- Sinusitis: occurs as an aspergilloma, acute or chronic sinus disease. Normal and immunocompromised patients can be affected. Associated with nasal polyps and aspirin allergy in normal hosts.
- ABPA: an IgE-mediated hypersensitivity response to inhaled spores. Most commonly occurs in settings of chronic lung disease (cystic fibrosis, asthma). Often have wheezing, productive cough with brown sputum. Diagnostic criteria include +skin test to Aspergillus antigens, serum IgE >1,000 ng/mL, transient infiltrates on chest x-ray, total eosinophil count >500 cells/microliter.
- Aspergilloma: fungus balls that grow in preexisting lung cavities (congenital, secondary to TB, sarcoid, chronic lung disease)
- Invasive pulmonary aspergillosis occurs in the immunocompromised host, most commonly following bone marrow or solid organ transplants, and patients with hematologic malignancy or primary immunodeficiency. Invasion of blood vessels by Aspergillus leads to infarction, necrosis, and hematogenous dissemination; resulting pulmonary hemorrhage is often fatal.
- Invasive aspergillosis in immunocompromised hosts can disseminate to the sinuses, brain, or skin. Rarer infections include endocarditis, meningitis, osteomyelitis, esophagitis, or infection of the eye.
Diagnosis
History
- Otomycosis: ear pain, pruritus, hearing loss
- Sinusitis: environmental allergies, chronic congestion, sinusitis unresponsive to antibiotics
- ABPA: unexplained worsening of asthma symptoms, cough productive of dark mucous plugs
- Lung disease: exposure to construction site or gardening (especially involving mulch or compost)
- Immunity: Is the patient immunocompromised?
- Immunocompromised patients, especially those with prolonged neutropenia, are at highest risk for invasive aspergillosis.
Physical Exam
- Cutaneous: necrotic-appearing painful ulcer
- Otomycosis: relapsing otorrhea with thick greasy exudate and pain on tragal movement. Black spores (A. niger) may be visible in the canal. Rarely invasive but may cause facial nerve palsy if it is.
- Sinusitis: Nasal obstruction, polyps, facial pain, and proptosis are typically seen. Invasive sinus aspergillosis may also cause monocular blindness and bony destruction on radiographic films, with erosion into the orbit or the cranial vault, or with widespread dissemination. The maxillary sinuses are most commonly involved.
- Lung disease: often indistinguishable from other causes of pneumonia on physical examination. Fever, tachypnea, rales, hypoxemia, and hemoptysis (due to angioinvasion) may be present.
Diagnostic Tests & Interpretation
Lab & Radiography
- Aspergillus can be isolated from nearly any body site including blood, cerebrospinal fluid, sputum, urine, bronchoalveolar lavage (BAL) fluid, and tissue biopsy specimens.
- Respiratory specimens growing Aspergillus spp. on culture (e.g., sputum and nasal cultures) may represent colonization in the immunocompetent host but may indicate invasive disease in certain hosts. The entire clinical picture including history and physical exam should be considered when interpreting culture results.
- Presence of branching, septate hyphae on stained biopsy specimens or a wet preparation performed with 10% potassium hydroxide (KOH) is suggestive of Aspergillus or other mold species.
- Cutaneous aspergillosis, otomycosis, and sinusitis: Suggestive lab findings include biopsy culture growing Aspergillus sp., pathology specimen with septate hyphae on KOH preparation in the setting of a consistent clinical picture.
- Sinusitis and ABPA: may also see elevated serum IgE, eosinophilia, Aspergillus-specific serum IgE, and an immediate-type skin test response to Aspergillus antigen which may support diagnosis
- Isolation of Aspergillus sp. by culture is ideal but often does not occur in pulmonary and disseminated disease.
- Radiographic studies may support the diagnosis but are not definitive.
- ABPA: centrilobular nodules, "finger in glove," upper lobe infiltrate
- Pulmonary disease: cavitations, nodules (seen in ~35%). Classic CT findings of "halo sign" (an area of low attenuation surrounding a nodule) initially and later the "crescent sign" (an air crescent near the periphery of a lung nodule, caused by contraction of infarcted tissue) are seen infrequently in children but may be present in adolescents.
- Adjunctive tests: Galactomannan is a polysaccharide of Aspergillus cell walls. Enzyme immunoassay (EIA) for galactomannan from serum or BAL fluid early in the course may aid diagnosis of aspergillosis in immunocompromised children.
Differential Diagnosis
- Bacterial sinusitis, otitis, or pneumonia
- Asthma, cystic fibrosis
- Nocardia, Streptococcus pneumoniae, and Staphylococcus aureus can cause similar-appearing pulmonary lesions.
Treatment
Medication
First Line
Voriconazole is primary therapy for invasive aspergillosis. Treatment is generally at least 12 weeks. Therapeutic drug monitoring should be performed because of interpatient variability.
Second Line
- Echinocandins (micafungin, caspofungin)
- Amphotericin B and the lipid-based amphotericin products can be used for salvage therapy or empirically in cases when mold is suspected and zygomycetes cannot be ruled out. Lipid-based products tend to have less toxicity and may be better tolerated.
- Posaconazole: requires that patients tolerate a fatty diet for optimal absorption
- Itraconazole is occasionally used as step-down therapy for mild to moderate aspergillosis, but with newer agents, this is rarely necessary.
Additional Therapies
General Measures
- Otomycosis: As it is often a coinfection with bacterial external otitis, treatment of the bacterial infection and debridement of canal debris is usually curative. Otic antifungal preparations or acetic acid may be considered if the tympanic membrane is intact.
- Sinusitis: If noninvasive, surgical drainage or debridement is usually curative.
- ABPA: First-line therapy is oral steroids. Addition of itraconazole or voriconazole may help refractory cases.
- Aspergilloma: Surgical excision is necessary as antifungals cannot penetrate cavitation well.
Surgery/Other Procedures
Surgical excision or localized debridement, in addition to antifungal medication, may be required for invasive disease. Mortality may be improved with surgical excision of lung lesions, but the procedure itself is often risky.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
Ongoing infections should be carefully monitored with serial radiographic studies as complications can be severe.
Alert
- The classic radiographic findings of pulmonary aspergillosis are infrequently seen in children and their absence should NOT be used to eliminate Aspergillus as the causative agent.
- Evaluation for Aspergillus should be performed in immunocompromised patients with persistent fever who do not improve on broad-spectrum antibiotics; empiric antifungals should be considered.
- Aspergillosis in a normal host often does not require antifungal therapy.
Prognosis
- Noninvasive disease (otomycosis, sinusitis) in the normal host usually resolves but may take several weeks.
- ABPA has variable outcomes: Resolution, steroid dependence, and ongoing lung destruction due to inflammatory dysregulation are all possible.
- Immunosuppressed or neutropenic patients may have rapid extension or dissemination of disease; prognosis is often very poor. Early recognition and aggressive treatment and debridement are necessary.
Complications
- Progression to invasive disseminated disease can occur as the initial manifestation if host factors are altered. Involvement of CNS, heart, or bones worsen prognosis.
- Otitis and sinusitis can erode through cranial bones to involve the orbits or CNS.
- Pulmonary disease can progress to pulmonary hemorrhage as angioinvasion occurs; respiratory failure or pneumothorax may develop as lung tissue is destroyed.
Additional Reading
- Burgos A, Zaoutis TE, Dvorak CC, et al. Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics. 2008;121(5):e1286-e1294. [View Abstract]
- Choi SH, Kang ES, Eo H, et al. Aspergillus galactomannan antigen assay and invasive aspergillosis in pediatric cancer patients and hematopoietic stem cell transplant recipients. Pediatr Blood Cancer. 2013;60(2):316-322. [View Abstract]
- Huppmann MV, Monson M. Allergic bronchopulmonary aspergillosis: a unique presentation in a pediatric patient. Pediatr Radiol. 2008;38(8):879-883. [View Abstract]
- Schubert MS. Allergic fungal sinusitis: pathophysiology, diagnosis and management. Med Mycol. 2009;47(Suppl 1):S324-S330. [View Abstract]
- Stevens DA, Melikian GL. Aspergillosis in the "nonimmunocompromised" host. Immunol Invest. 2011;40(7-8):751-766. [View Abstract]
- Vennewald I, Klemm E. Otomycosis: diagnosis and treatment. Clin Dermatol. 2010;28(2):202-211. [View Abstract]
- Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327-360. [View Abstract]
Codes
ICD09
- 117.3 Aspergillosis
- 484.6 Pneumonia in aspergillosis
- 518.6 Allergic bronchopulmonary aspergillosis
- 380.15 Chronic mycotic otitis externa
- 495.9 Unspecified allergic alveolitis and pneumonitis
ICD10
- B44.9 Aspergillosis, unspecified
- B44.1 Other pulmonary aspergillosis
- B44.81 Allergic bronchopulmonary aspergillosis
- B44.89 Other forms of aspergillosis
- B44.0 Invasive pulmonary aspergillosis
- B44.7 Disseminated aspergillosis
- B44.2 Tonsillar aspergillosis
SNOMED
- 65553006 Aspergillosis (disorder)
- 6042001 Pulmonary aspergillosis (disorder)
- 37981002 Allergic bronchopulmonary aspergillosis (disorder)
- 302905001 Aspergillus otomycosis (disorder)
- 3214003 Invasive pulmonary aspergillosis (disorder)
FAQ
- Q: Is aspergillosis contagious?
- A: No. Disease is acquired by inhalation of airborne spores. People living or working in the same environment may be exposed to similar amounts of spores so clusters of infection are possible.