eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Aspergillosis

Author: Vandana Batra, MD, Pediatrician, Department of Pediatrics, Division of General Pediatrics/Primary Care, Nemours Pediatrics
Coauthor(s): Basim Asmar, MD, Director, Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan; Professor, Department of Pediatrics, Wayne State University School of Medicine; Jocelyn Y Ang, MD, Assistant Professor, Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan and Wayne State University
Contributor Information and Disclosures

Updated: Oct 17, 2008

Introduction

Background

Ubiquitous saprophytic molds, Aspergillus species are common on decaying material throughout the world. More than 900 species are included in the genus Aspergillus. The agent responsible for more than 90% of human infections is Aspergillus fumigatus. Aspergillus flavus accounts for about 10% of invasive disease; Aspergillus niger and Aspergillus terreus each are responsible for approximately 2% of all invasive diseases. Other pathogens of interest include Aspergillus amstelodami, Aspergillus avenaceus, Aspergillus caesiellus, Aspergillus carneus, Aspergillus clavatus, Aspergillus oryzae, Aspergillus versicolor, and Aspergillus wentii. The most common cause of sinusitis is A flavus; the predominant cause of otomycosis is A niger.

Aspergillus species are characterized by dichotomously branching septate hyphae. Conidiophores are tubular structures arising from the hyphae, and the terminal ends of these widen to form vesicles. Spores or conidia are formed from long chains of sterigmata, which cover these vesicles. Abundant sporulation is demonstrated by every conidial head producing numerous conidia. These conidia are easily airborne, and their small size (ie, 2-3 µm) aids access to the lower respiratory tract. Characteristically, A fumigatus organisms are identified by the morphology of the conidia and conidiophores. A fumigatus organisms have green echinulate conidia produced basipetally from greenish phialides.

Pathophysiology

In most patients, the respiratory tract is the usual portal of entry and site of infection. Disease is classified by the site involved within the respiratory tract and by the extent of mycelial colonization or invasion of tissue, both of which are influenced by the host's immune status. Allergic disease (eg, allergic sinusitis, asthma, alveolitis) occurs following repeated exposure to Aspergillus conidia or antigens in patients without mycelial colonization or invasion. In contrast, allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, and invasive aspergillosis syndrome involve mycelial growth in the body of the host.

Noninvasive aspergillosis is usually seen in immunocompetent individuals, whereas invasive aspergillosis is seen in immunocompromised patients. Noninvasive disease usually manifests as allergic bronchopulmonary aspergillosis, aspergilloma, and allergic sinusitis, whereas invasive disease can lead to widespread organ involvement, including pulmonary, cerebral, ocular, and cutaneous disease.

The histopathologic/cytopathologic view of invasive aspergillosis from a needle aspiration or biopsy demonstrates septate acutely branching hyphae or spherule formation (filamentous fungi without yeast forms), with evidence of associated tissue damage (either microscopically or unequivocally by imaging). Probable cases of invasive aspergillosis have been defined to include those with a clinically documented site of infection, and a culture from this site positive for Aspergillus species. Clinically documented infection is defined when fever is accompanied by cellulitis, sinusitis, pneumonia, or esophagitis. Possible invasive aspergillosis is defined as a clinically documented infection with undetermined microbiological etiology that did not respond to antibacterial therapy during persistent neutropenia.

Allergic bronchopulmonary aspergillosis

The pathogenesis of ABPA involves allergic reactions to Aspergillus species. Patients with chronic respiratory disease (eg, asthma, cystic fibrosis [CF]) may trap A fumigatus in their tenacious secretions, leading to an immune response that exacerbates their respiratory symptoms. Chronic mucosal colonization with A fumigatus causes elevated immunoglobulin G (IgG) and immunoglobulin E (IgE) levels, which lead to recurrent bronchospasm. ABPA occurs in 1-2% of patients with asthma and in 11% of patients with CF.

Aspergilloma

Aspergilloma is a nonallergic colonization by Aspergillus species in patients who are immunocompetent. Preexisting pulmonary cavities form a nidus for aspergilloma. These include cavities caused by tuberculosis, sarcoidosis, and chronically obstructed paranasal sinuses.

Invasive aspergillosis

Aspergillus disseminates by means of conidia, which disperse readily throughout the environment because of their lightweight. Airborne conidia enter the human host via inhalation or inoculation. An increase in the environmental load of conidia leads to increased risk of disease. Construction or renovation of hospital buildings or demolition of air-handling ducts near hospitals may lead to outbreaks of aspergillosis, especially in patients who are immunocompromised because these actions release concentrated bursts of conidia, which contaminate the surroundings.

Phagocytic cells, including pulmonary macrophages and neutrophils, are the first lines of defense against the conidia that are inhaled into the respiratory tract. Hyphae are destroyed by neutrophils, and macrophages ingest the conidia. This is why patients with immunocompromising conditions (eg, patients preparing for bone marrow transplantation, patients with graft versus host disease or graft rejection) have the highest risk of developing invasive aspergillosis.

Aspergillus species are second only to candida organisms as the cause of opportunistic infections in patients who are immunocompromised. Profound neutropenia (ie, polymorphonuclear leucocytes <100/μL) and prolonged neutropenia (>12-15 d) create significant risks of patients developing invasive aspergillosis. Patients on corticosteroid therapy, cytotoxic chemotherapy, intravenous drug use, and broad-spectrum antimicrobial therapy also have increased susceptibility to invasive aspergillosis. Allogenic hematopoietic stem cell transplantation (HSCT) recipients are at much higher risk of invasive aspergillosis compared with autologous HSCT recipients, especially in the first month of conditioning regimens, which usually lead to profound neutropenia.

Functional neutrophil defects, including defective oxidative killing, are responsible for invasive aspergillosis that occurs in chronic granulomatous disease. Defects in cell-mediated immunity alone rarely predispose patients to invasive aspergillosis. For example, invasive aspergillosis occurs only in patients with advanced acquired immunodeficiency syndrome (AIDS) when significant neutrophil dysfunction occurs.

In patients who are immunosuppressed, widespread dissemination of Aspergillus is secondary to vascular invasion. This angiotropism is associated with infarction and tissue necrosis. In addition to pulmonary involvement, other sites of infection include the brain, skin, GI tract, kidneys, and peritoneum.

Frequency

United States

Frequency in the United States is similar to international frequency.

International

The incidence of invasive aspergillosis varies according to the underlying condition. The incidence is 19-26% in patients who have undergone heart and lung transplantation, 25-40% in patients with chronic granulomatous disease, 5-24% in patients with acute leukemia, and 3-7% in patients undergoing bone marrow transplantation. ABPA incidence rates are unavailable; however, the frequency of ABPA is increasing because of the increasing incidence of asthma. The incidence of aspergillomas is declining.

Mortality/Morbidity

The mortality rate of invasive aspergillosis ranges from 45-94%. CNS involvement is invariably fatal.

Race

Aspergillosis equally affects all races.

Sex

Aspergillosis equally affects both sexes.

Age

Aspergillosis may affect individuals at any age.

Clinical

History

Patient history depends on whether the Aspergillus infection is invasive or noninvasive. Invasive aspergillosis (IA) includes acute and chronic pulmonary aspergillosis, tracheobronchitis, sinusitis, and disseminated disease, such as CNS involvement. Disseminated disease is the more severe manifestation and is defined as involvement of 2 or more contiguous organs.

• Invasive aspergillosis
  • Acute invasive pulmonary aspergillosis: Pulmonary disease occurs in 80-90% of patients with invasive aspergillosis. Fever, dyspnea, nonproductive cough, mild hemoptysis, and pleuritic chest pain are the cardinal clinical manifestations of invasive pulmonary aspergillosis. Severely immunocompromised patients may have no initial symptoms but diagnosis warrants a high index of suspicion.
  • Chronic invasive pulmonary aspergillosis usually occurs in patients with underlying diseases (eg, advanced AIDS, chronic granulomatous disease, sarcoidosis, diabetes mellitus). Patients usually complain of chronic nonproductive cough, often with hemoptysis. Low-grade fever, weight loss, and malaise are also common.
  • Tracheobronchitis caused by Aspergillus species usually occurs in lung transplant recipients and patients with advanced AIDS. Most of these patients experience symptoms including fever, cough, hemoptysis, dyspnea, and chest pain. Occlusion of the airways may result in death if the condition remains undiagnosed and untreated.
  • Patients with sinusitis caused by Aspergillus species usually complain of headache. Other symptoms include fever, cough, epistaxis, nasal discharge, sinus pain, and sore throat.
  • Primary involvement of the skin rarely occurs; the skin is more commonly a secondary site of hematogenous spread from a pulmonary infection. Surgical wounds, burn wounds, vascular catheters, and adhesive dressing applied to the skin may predispose to the development of cutaneous aspergillosis, especially in immunocompromised patients. The usual presentation of skin involvement is the appearance of raised red lesions, which may progress to ulceration and eschar formation.
  • Cerebral involvement almost always occurs in patients who are neutropenic and in those undergoing bone marrow or solid organ transplantation. Patients that are severely immunocompromised usually present with altered mentation and seizures; prognosis is dismal. Fever is uncommon.
  • Patients with Aspergillus endophthalmitis may complain of pain, photophobia, and diminished visual acuity. Most of these patients have no other systemic symptoms. Orbital cellulitis may complicate invasive sinusitis. The patient may present with pain on lateral gaze and diplopia.
• Noninvasive aspergillosis
  • Patients with allergic bronchopulmonary aspergillosis (ABPA) often have histories of worsening respiratory symptoms in association with asthma or cystic fibrosis (CF). ABPA occurs in approximately 11% of patients with CF. The main complaints of these patients are wheezing and cough. As the disease progresses, patients may expectorate mucous plugs containing eosinophils, and they may develop bronchiectasis.
  • Exacerbation and remission characterize the natural history of disease. Progression to respiratory failure may occur occasionally because of irreversible airway obstruction and pulmonary fibrosis. It may mimic pneumonia with mucopurulent bloody sputum, fever, and respiratory distress. Predominant wheezing may be the only manifestation suggesting an exacerbation of bronchial asthma.
  • The staging system developed by Greenberger and Patterson (1986) classifies ABPA into 5 stages, as follows:¹
    • Stage I (acute): The patient exhibits moderate or severe asthma, a productive cough, and infiltrates on chest radiograph.
    • Stage II (remission): The patient has mild or no asthma following steroid treatment. Serum immunoglobulin E (IgE) levels decline. The patient may remain in Stage II permanently or may progress to further disease.
    • Stage III (recurrent exacerbation): Exacerbation with the appearance of new infiltrates, elevated IgE, and eosinophilia.
    • Stage IV (corticosteroid dependent asthma): Tapering doses of steroids leads to acute exacerbation or recurrence of disease.
    • Stage V (fibrotic lung disease): The diagnosis is based on pulmonary fibrosis on radiograph. Irreversible deterioration in pulmonary function occurs, which cannot improve, even with steroid therapy.
  • Patients with allergic fungal rhinosinusitis usually have symptoms of long-standing sinusitis. The patient may have a history of nasal polyposis, prior nasal surgery, or atopic disease. Rubbery particles composed of tenacious allergic mucin may be expectorated.
  • Aspergillomas may remain asymptomatic until hemoptysis occurs.

Physical

Physical signs of aspergillosis include the following:

• Pulmonary
  • Initially, 25-33% of patients with acute invasive pulmonary aspergillosis may have no obvious clinical signs. In some cases, physical findings may reveal a pleural rub.
  • Patients with extensive involvement may be hypoxemic.
  • Pneumothorax is occasionally a presenting feature, and breathing sounds on auscultation may decrease and exhibit hyperresonance on percussion.
  • Patients with chronic granulomatous disease may have local extension into the chest wall, brachial plexus, or vertebral column.
• Cutaneous: Cutaneous lesions present as erythematous papules or nodules, which progressively enlarge, ulcerate, and are covered by a black necrotic crust. Patients with central venous catheter associated aspergillosis may develop hemorrhagic bullous skin lesions. Disseminated disease may lead to multiple papulopustular or macular lesions in the extremities. These lesions may ulcerate with eschar formation.
• Cerebral
  • Severely immunocompromised patients who have cerebral aspergillosis may present with nonspecific findings (eg, altered mental status, seizures).
  • Patients with less immunocompromising conditions are more likely to present with focal features, such as hemiparesis, cranial nerve palsies, or focal seizures.
  • Papilledema and meningeal signs are uncommon.
• Sinusitis
  • Patients with sinusitis usually have dark nasal lesions, with or without nasal discharge.
  • Sinus tenderness, nasal or oral ulceration, and duskiness or necrosis of the nasal septum and inferior turbinates may occur.
  • Facial swelling is unusual, and extension into the brain or orbit may cause proptosis or focal neurological signs (eg, hemiparesis, cranial nerve palsies, focal seizures).
• Eye
  • Retinal examination of patients with fungal endophthalmitis may reveal focal retinitis, vitreitis, and retinal hemorrhage.
  • Periorbital edema and proptosis may occur with orbital cellulitis.

Causes

• Patients with granulocytopenia or defects in neutrophil function secondary to underlying illness have increased risk of developing invasive aspergillosis. Other predisposing factors for acquiring invasive aspergillosis include the following:
  • Corticosteroid and cytotoxic chemotherapy
  • Quantitative immunodeficiencies (eg, chronic granulomatous disease)
  • Advanced AIDS
  • Bone marrow transplant
  • Solid organ transplant
  • Graft versus host disease
  • Graft rejection
• ABPA usually occurs in patients with CF or underlying bronchial asthma.
• Aspergilloma usually occurs in preexisting pulmonary cavities such as in cysts caused by tuberculosis or sarcoidosis.

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