Stephen C. Aronoff

Aspergillosis refers to a group of diseases caused by monomorphic, mycelial fungi of the genus Aspergillus. Most diseases in children are caused by A. fumigatus; less frequently, A. flavus and A. niger are the causative agents. A. nidulans and A. terreus have also been reported in pediatric infections. Aspergilli are distributed worldwide, and spores (conidia) are readily isolated from soil and decaying plants. Outbreaks of invasive disease among immunosuppressed children may occur after they have been exposed to aerosolized conidia at construction sites near hospitals and clinics. Infection is usually acquired from inhalation of airborne spores, which colonize the upper and lower respiratory tracts. Immunocompromised persons are at risk for hematogenous dissemination. Cutaneous infection is also common and may follow wound contamination, intradermal inoculation, or hematogenous dissemination. Ingestion and aspiration may also produce disease. Aspergillus-associated diseases may be immunoglobulin (Ig) E mediated (hypersensitivity syndromes), saprophytic (noninvasive), or invasive.


233.1 Hypersensitivity Syndromes


Atopic asthma may be precipitated by inhalation of Aspergillus spores, which triggers an IgE-mediated response and bronchospasm. The clinical symptoms are nonspecific and include the acute onset of wheezing in the absence of pulmonary infiltrates or fever.


Extrinsic alveolar alveolitis is a hypersensitivity pneumonitis that occurs in nonatopic individuals after repeated exposures to organic dust. Aspergillus is one of many organic substances that produce this syndrome ("malt worker's" or "farmer's" lung). The pathogenesis is unknown but is similar to the alveolitis caused by other immunogens and may represent an immune complex disease. The clinical manifestations typically follow exposure by 4-6hr and include fever, cough, and dyspnea. Physical examination often reveals rhonchi without wheezes. Eosinophilia is absent from blood and sputum, and chest radiograph often shows diffuse interstitial infiltrates. Chronic exposure gradually leads to irreversible pulmonary fibrosis.


Allergic bronchopulmonary aspergillosis complicates chronic pulmonary disease in approximately 10% of children with asthma or cystic fibrosis. Chronic mucosal colonization with A. fumigatus produces an exaggerated IgG and IgE response, which results in recurrent bronchospasm and proximal cylindrical bronchiectasis. The diagnosis should be considered in patients with asthma or cystic fibrosis who have recurrent bronchospasm and transient pulmonary infiltrates. Expectoration of mucous spirals containing mycelia is a hallmark of this illness; peripheral eosinophilia is common. The diagnosis of allergic bronchopulmonary aspergillosis requires fulfillment of the following criteria: (1) reversible paroxysmal bronchiolar obstruction (asthma); (2) immediate cutaneous reactivity to A. fumigatus antigens or specific serum IgE to A. fumigatus (radioallergosorbent [RAST] test); (3) elevated total serum IgE; (4) peripheral blood eosinophilia; (5) precipitating serum antibodies against A. fumigatus; and (6) proximal bronchiectasis.


Treatment of the hypersensitivity pulmonary syndromes focuses on anti-inflammatory agents, notably corticosteroids, and bronchodilator therapy. Growing experience with itraconazole in older adolescents and young adults with allergic bronchopulmonary dysplasia has demonstrated the potential benefit of this drug when used in combination with corticosteroid therapy.

233.2 Saprophytic (Noninvasive) Syndromes


Otomycosis is a chronic condition that is found predominantly in tropical and subtropical regions and is rare in infants and children. Most infections are due to A. niger or, less commonly, A. fumigatus; coinfection with Staphylococcus aureus or Pseudomonas species occurs in one third of cases. Most cases are unilateral, and patients present with ear pain, itching of the auditory canal, and a sense of fullness. Otorrhea, decreased hearing, and tinnitus are less common. Examination of the auditory canal typically shows conidial "forests" or mycelial mats. Topical antifungal agents such as nystatin, tolnaftate, dilute acetic acid, and topical corticosteroids are therapeutic. Oral itraconazole has also been effective, but experience with it is limited.



Aspergillus noninvasive sinonasal disease may present in three forms. Chronic or indolent sinusitis is confined to one sinus and presents as a chronic infection that is unresponsive to antibacterial therapy. Sinus radiograms are nonspecific, showing mucosal thickening without bony changes. Endoscopic surgery is curative in most cases. Sinus aspergilloma, which is rare in children, presents with long-standing nasal symptoms. Sinus radiographs demonstrate a solitary mass in the ethmoid or maxillary sinus. Bony destruction is variable. Surgical removal of the mass, often endoscopically, is the treatment of choice. Allergic fungal sinusitis involves multiple sinuses and occurs in immunocompetent individuals who usually have a history of multiple preceding sinus surgeries and nasal polyposis. Aspergillus species and less often Curvularia lunata are the usual etiologic agents. Histology of nasal secretions in these patients reveals thick mucin, eosinophils, and few fungal hyphae. Sinus imaging typically shows involvement of multiple sinuses with hypodense areas, occasional calcifications, and occasional bony erosions. Criteria for the diagnosis of allergic fungal sinusitis are immunologic and are identical to those listed for allergic bronchopulmonary aspergillosis, which may complicate allergic fungal sinusitis. Treatment includes surgical drainage and debridement as well as corticosteroid therapy.


Pulmonary aspergillomas develop in poorly drained bronchi or pre-existing pulmonary cavities and may complicate pulmonary tuberculosis, histoplasmosis, blastomycosis, or sarcoidosis; rarely, aspergillomas complicate invasive Aspergillus pulmonary disease. Colonization and fungal proliferation occur in the cavity, but no vascular invasion occurs; an amorphous mycelial mass (mycetoma, fungus ball) results. Affected children are often asymptomatic, although cough and hemoptysis may be reported. Chest radiographs characteristically demonstrate the air shadow of a pulmonary cavity outlining a rounded mass; these findings may be confirmed by computed tomography of the chest. Management is controversial and may range from watchful waiting for asymptomatic and otherwise healthy children to surgical resection in patients with symptoms.

233.3 Invasive Disease


Invasive Aspergillus infection is characterized by hyphal infiltration of vascular structures, thrombosis, and focal necrosis. Invasive disease occurs most commonly in immunocompromised patients, particularly neutropenic children with leukemia, children with human immunodeficiency virus (HIV) infection, bone marrow transplant recipients, and, less commonly, solid organ recipients. Primary invasive disease may occur at any site in which airborne conidia may colonize and germinate, such as the respiratory tract or skin. In the severely neutropenic child, dissemination follows direct extension from the primary site and hematogenous seeding of distant sites. Sinonasal disease, pulmonary disease, and cutaneous disease are the most common primary infections in children. Otitis media is rare. Although systemic amphotericin B (either desoxycholate or the liposomal formulations) remains the recommended treatment for most established Aspergillus infections, the outcome appears to hinge on resolution of the underlying immunocompromised state. Itraconazole, a triazole antifungal agent, has appreciable in vitro activity against Aspergillus species, but experience with this agent for the treatment of aspergillosis in children is limited. Aerosolized amphotericin B is currently under investigation for prophylaxis in cancer patients during periods of profound neutropenia.



Otitis externa associated with Aspergillus infection is rare, occurs in immunosuppressed individuals, and is associated with hearing loss and spread to the petrous portion of the temporal bone and the pinna. Therapy includes amphotericin B and surgical debridement; experience with itraconazole is limited.


Nasosinusitis occurs almost exclusively in patients with profound neutropenia associated with chemotherapy for cancer and is rare in children. Fever, cough, epistaxis, headache, and sinus pain are the most common clinical signs. Examination typically shows nasal crusting with rhinorrhea, sinus tenderness, nasal or oral ulceration, and duskiness or necrosis of the nasal septum or inferior turbinates. Multiple sinus involvement with opacification or air-fluid levels can be demonstrated radiographically or by computed tomography. Scrapings of the nasal or sinus mucosa demonstrate large numbers of hyphae, and fungal cultures typically yield A. fumigatus, A. flavus, or, less often, Rhizopus or Candida species.

Treatment is not standardized but often includes surgical drainage, intravenous and intranasal amphotericin B, and removal of devascularized necrotic tissue. Extensive surgical procedures are often hampered by underlying thrombocytopenia and extensive and at times life-threatening hemorrhage. Sporadic treatment successes and failures have been reported with itraconazole; however, comparative data with amphotericin B are not available. Invasive sinusitis has a poor prognosis for children with leukemia in relapse; better outcomes occur with resolution of the granulocytopenia or remission of the underlying disease.


Invasive pulmonary aspergillosis is the most common form of Aspergillus infection and usually occurs in immunocompromised patients. The onset is often insidious. In both immunocompetent and immunocompromised patients, symptomatic infection presents acutely with fever, cough, dyspnea, and abnormal chest findings; pleuritic chest pain is an infrequent complaint. Chest radiographs often show nodular infiltrates. Coexisting sinusitis is a common finding in neutropenic children. In children with chronic granulomatous disease, direct extension from the lungs to the chest wall has been reported.

The diagnosis is confirmed by histologic demonstration of hyphal invasion of blood vessels and recovery of the fungus by culture of the biopsy specimen. Recovery of a pure culture of Aspergillus species from two sputum samples from immunocompromised patients with nodular, cavitary, or wedge-shaped lesions on chest radiographs is highly suggestive of invasive disease.

Treatment with high-dose amphotericin B (1mg/kg/24hr) for 4-6wk, or until the neutropenia resolves or the underlying disease goes into remission, is recommended. Experience with itraconazole is limited.


Cutaneous aspergillosis is a common manifestation of invasive aspergillosis in immunocompromised children. Lesions are typically seen at sites of local trauma such as intravenous sites. Cutaneous disease may result either from direct inoculation of the skin or, more frequently, from hematogenous dissemination. The lesions appear initially as tender erythematous plaques that progress to necrotic eschars or hemorrhagic bullae (ecthyma gangrenosum). In the majority of children with profound neutropenia, cutaneous aspergillosis is a sentinel marker of disseminated disease and indicates a poor outcome. Treatment with high-dose amphotericin B (1mg/kg/24hr) is recommended for 4-6wk, or until the neutropenia resolves or the underlying disease goes into remission. Local debridement and topical amphotericin have also been used. Experience with itraconazole is limited.


Fungal endophthalmitis is an important diagnostic finding in immunosuppressed children with disseminated Aspergillus infection. Although most patients have no ocular symptoms, pain, photophobia, and diminished visual acuity may occur. Examination of the retina shows focal retinitis, an overlying vitreitis, and retinal hemorrhage. Treatment of the underlying immunosuppressive illness, systemic antifungal therapy,


vitrectomy, and intraocular amphotericin B are recommended. Amphotericin B and itraconazole achieve poor intraocular concentrations.


Orbital cellulitis rarely complicates invasive sinusitis and follows destruction of the orbital walls and fungal extension into the retro-orbital space. Diplopia, periorbital edema, proptosis, and pain on lateral gaze may occur. Treatment requires a combination of surgical debridement, systemic antifungal therapy, and resolution of the underlying immunocompromised state.

Fungal keratitis and episcleritis are rare problems and follow direct inoculation of spores into the eye. In the absence of significant disseminated disease, topical and intrascleral amphotericin B therapy is recommended.


Cerebral aspergillosis is a rare and almost uniformly fatal complication of disseminated disease. In most cases, infection involves single or multiple foci within the cerebral hemispheres or cerebellum. Focal neurologic deficits begin acutely, most often hemiparesis, anterior cranial nerve palsies, or seizures. Progression to herniation is rapid. Meningeal signs are rare, and at autopsy arachnoiditis is limited to the area adjacent to the cerebral focus. Cerebrospinal fluid shows a mild mononuclear pleocytosis, elevated CSF protein, and variable degrees of hypoglycorrhachia. Imaging studies demonstrate focal central nervous system lesions with edema and variable enhancement. The diagnosis can be established by the acute appearance of neurologic symptoms in a patient with proven or suspected invasive aspergillosis or occasionally by cerebrospinal fluid or brain biopsy culture. High-dose amphotericin B combined with flucytosine has been effective in a paucity of cases.

Epidural abscess is a rare complication of vertebral osteomyelitis caused by Aspergillus species. In two children with epidural abscess, vertebral osteomyelitis and cord compression, surgical decompression, and high-dose amphotericin B were curative.


Aspergillosis of the bone is an extremely rare disease and follows direct extension of infection from a surgical or traumatic wound or hematogenous seeding. Involvement of the vertebrae is most common. Osteomyelitis of the rib is rare, occurs in children with chronic granulomatous disease, and represents extension from a pulmonary focus. Surgical drainage is often required. Although comparative studies are not available, initial therapy with amphotericin B plus flucytosine followed by itraconazole is a promising approach.


Endocarditis is a rare form of aspergillosis and can follow contamination at the time of surgery or implantation of a contaminated graft, or, uncommonly, it may be a manifestation of disseminated aspergillosis. High-dose amphotericin B therapy coupled with surgical removal of infected grafts or prostheses is recommended.

Denning DW, Stevens DA: Antifungal and surgical treatment of invasive aspergillosis: Review of 2121 published cases. Rev Infect Dis 12:1147, 1990.

Horvath JA, Dummer S: The use of respiratory tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med 100:171, 1996.

Neijens HJ, Frenkel J, et al: Invasive Aspergillus infection in chronic granulomatous disease: Treatment with itraconazole. J Pediatr 115:1016, 1989.

Walmsley S, Devi S, King S, et al: Invasive Aspergillus infections in a pediatric hospital: A ten-year review. Pediatr Infect Dis J 12:673, 1993.

Wong-Beringer A, Jacobs RA, Guglielmo BJ: Lipid formulations of amphotericin B: Clinical efficacy and toxicities. Clin Infect Dis 27:603, 1998.

This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. We are making such material available in our efforts to advance understanding of environmental, political, human rights, economic, democracy, scientific, and social justice issues, etc. We believe this constitutes a 'fair use' of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes. For more information go to: If you wish to use copyrighted material from this site for purposes of your own that go beyond 'fair use', you must obtain permission from the copyright owner.

[return to menu]


2001 Mold-Help All rights reserved.