Practice Essentials

Aspergillus primarily affects the lungs, causing 4 main syndromes: allergic bronchopulmonary aspergillosis (ABPA), chronic
necrotizing Aspergilluspneumonia (also termed chronic necrotizing pulmonary aspergillosis [CNPA]), aspergilloma, and invasive
aspergillosis. However, in patients who are severely immunocompromised, Aspergillus may hematogenously disseminate beyond the lungs.
Essential update: FDA approves IV antifungal posaconazole
The FDA has approved an intravenous formulation of the triazole antifungal posaconazole (Noxafil), which is indicated for the prophylaxis of
invasiveAspergillus and Candida infections in severely immunocompromised adults who are at high risk of developing these infections.
Posaconazole injection is administered as a loading dose of 300 mg twice on the first day of treatment, followed by 300 mg once daily
thereafter. Posaconazole is also available as a 100-mg delayed-release tablet and in a 40 mg/mL oral suspension.
[1]

Signs and symptoms
Allergic bronchopulmonary aspergillosis
Occurs in persons with asthma and those with cystic fibrosis (CF)
May manifest as fever and pulmonary infiltrates unresponsive to antibacterial therapy
Patients often have a cough and produce mucous plugs, which may form bronchial casts; they may have hemoptysis
Patients with asthma and ABPA may have poorly controlled disease and difficulty tapering off oral corticosteroids
ABPA may occur in conjunction with allergic fungal sinusitis, with symptoms including chronic sinusitis with purulent sinus drainage
Wheezing may be noted upon auscultation of the chest; the patient may produce mucous plugs upon coughing
Aspergilloma
May manifest as an asymptomatic radiographic abnormality in a patient with preexisting cavitary lung disease due to sarcoidosis,
tuberculosis, or other necrotizing pulmonary processes
May occur in cystic areas resulting from prior Pneumocystis jirovecipneumonia in patients with HIV disease
Causes hemoptysis, which may be massive and life threatening, in 40-60% of patients
Less commonly, may cause cough and fever
Chronic necrotizing pulmonary aspergillosis
Occurs in patients with underlying disease (eg, steroid-dependent COPD, alcoholism)
Manifests as a subacute pneumonia unresponsive to antibiotic therapy, which progresses and cavitates over weeks or months
Symptoms may include fever, cough, night sweats, and weight loss
Invasive aspergillosis
Occurs in patients with prolonged neutropenia or immunosuppression
Typically manifests as fever, cough, dyspnea, pleuritic chest pain, and, sometimes, hemoptysis
Patients may be tachypneic and have rapidly progressive hypoxemia
Risk factors include organ transplantation, especially bone marrow but also lung, heart, and other solid organ transplants
In bone marrow transplant patients, invasive aspergillosis has a bimodal distribution, occurring early with prolonged neutropenia before
engraftment and later during high-dose corticosteroid therapy for graft-versus-host disease
In patients with leukemia and lymphoma, invasive aspergillosis may occur after chemotherapy-induced bone marrow suppression
Invasive aspergillosis is being increasingly observed in patients with COPD on long-term corticosteroid therapy
[2, 3]

See Clinical Presentation for more detail.
Diagnosis
Allergic bronchopulmonary aspergillosis
ABPA is defined by abnormalities including the following:
Asthma
Eosinophilia
A positive skin test result for A fumigatus
Serum IgE level > 1000 IU/dL
Positive test results for Aspergillus precipitins (primarily IgG but also IgA and IgM)
Minor criteria for diagnosis include positive Aspergillus radioallergosorbent assay test results and sputum culture
Chest radiography results in ABPA may vary from fleeting pulmonary infiltrates to mucoid impaction to central bronchiectasis. CT scanning is
helpful for better defining bronchiectasis, and images may show that apparent lobulated masses are mucus-filled dilated bronchi. Areas of
atelectasis related to bronchial obstruction from mucoid impaction may be present.
Diagnostic criteria for ABPA in persons with CF include the following:
Clinical deterioration, including coughing, wheezing, increased sputum production, diminished exercise tolerance, and diminished
pulmonary function
Total serum IgE level >1000 IU/mL, or a greater than 2-fold rise from baseline
Positive Aspergillus serology (Aspergillus precipitins or Aspergillus -specific IgG or IgE)
New infiltrates on chest radiographs or CT scans
Aspergilloma
Aspergilloma does not cause many characteristic laboratory abnormalities. Aspergillus precipitin antibody test results (ie, for IgG) are usually
positive.
Imaging study results are as follows:
Chest radiographs show a mass in a preexisting cavity, usually in an upper lobe, manifested by a crescent of air partially outlining a solid
mass
As the patient is moved onto his or her side or from supine to prone, the mass is observed to move within the cavity
CT scan images provide better definition of the mass within a cavity and may demonstrate multiple aspergillomas in areas of extensive
cavitary disease; scanning may be performed with the patient in the supine and prone positions to demonstrate movement of the mass
within the cavity
Invasive aspergillosis and CNPA
Definitive diagnosis of invasive aspergillosis or CNPA depends on the demonstration of the organism in tissue, as follows:
Visualization of the characteristic fungi using Gomori methenamine silver stain or Calcofluor
Positive culture result from sputum, needle biopsy, or bronchoalveolar lavage (BAL) fluid (however, a negative result does not exclude
pulmonary aspergillosis)
Weekly monitoring of serum levels of galactomannan, a major component of theAspergillus cell wall, can be used to screen patients who are
at high risk for the development of invasive Aspergillus infection.
[4, 5]
An elevated galactomannan level in BAL fluid may also be helpful for
early diagnosis of invasive aspergillosis.
Imaging study results in invasive aspergillosis are as follows:
Chest radiographic features are variable, with solitary or multiple nodules, cavitary lesions, or alveolar infiltrates that are localized or
bilateral and more diffuse as disease progresses
In early disease, CT scans may demonstrate a characteristic halo sign (ie, an area of ground-glass infiltrate surrounding nodular
densities)
[6]

In later disease, CT scans may show a crescent of air surrounding nodules, indicative of cavitation
Because Aspergillus is angioinvasive, infiltrates may be wedge-shaped, pleural-based, and cavitary, which is consistent with pulmonary
infarction
See Workup for more detail.
Management
Allergic bronchopulmonary aspergillosis
Oral corticosteroids (inhaled steroids are not effective)
Adding oral itraconazole to steroids in patients with recurrent or chronic ABPA may be helpful
[7, 8, 9, 10]

Patients who have associated allergic fungal sinusitis also benefit from surgical resection of obstructing nasal polyps and inspissated
mucus; nasal washes with amphotericin or itraconazole have also been used
Aspergilloma
Treatment is considered when patients become symptomatic, usually with hemoptysis
Oral itraconazole may provide partial or complete resolution of aspergillomas in 60% of patients
Intracavitary treatment, using CT-guided, percutaneously placed catheters to instill amphotericin alone or in combination with other drugs
(eg, acetylcysteine, aminocaproic acid), has been successful in small numbers of patients
[11]

Surgical resection is curative and may be considered for massive hemoptysis if pulmonary function is adequate
Bronchial artery embolization may be used for life-threatening hemoptysis in patients unlikely to tolerate surgery or in patients with
recurrent hemoptysis (eg, patients with CF in whom hemoptysis may be related to underlying bronchiectasis with or without
aspergilloma)
[12]

Invasive aspergillosis
Preventive therapy and rapid institution of therapy for suspected cases may be lifesaving
Prophylactic antifungal therapy and the use of laminar airflow (LAF) or high-efficiency particulate air (HEPA) filtration of patient rooms can
be effective
Voriconazole Drug of choice
[13]

Posaconazole, amphotericin B, or amphotericin B lipid formulations May be considered as empiric therapy in critically ill patients with
possible mucormycosis
Caspofungin In patients who are unable to tolerate, or are resistant to, other therapies
[14]

If possible, the level of immunosuppression should be decreased
Chronic necrotizing pulmonary aspergillosis
Antifungal therapy is with voriconazole or with itraconazole (if expense is an issue), caspofungin, or amphotericin B or amphotericin lipid
formulation
A prolonged course of therapy with the goal of radiographic resolution is needed
Reduction or elimination of immunosuppression should be attempted, if possible
Surgical resection may be considered when localized disease fails to respond to antifungal therapy
See Treatment and Medication for more detail.
Background
Aspergillus species are ubiquitous molds found in organic matter. Although more than 100 species have been identified, the majority of
human illness is caused byAspergillus fumigatus and Aspergillus niger and, less frequently, by Aspergillus flavus and Aspergillus clavatus.
The transmission of fungal spores to the human host is via inhalation. Also see the Medscape articles Dermatologic Manifestations of
Aspergillosis, Pediatric Aspergillosis, and Thoracic Aspergillosis Imaging.
Aspergillus may cause a broad spectrum of disease in the human host, ranging from hypersensitivity reactions to direct
angioinvasion. Aspergillus primarily affects the lungs, causing the following 4 main syndromes:
Allergic bronchopulmonary aspergillosis (ABPA)
Chronic necrotizing Aspergillus pneumonia (or chronic necrotizing pulmonary aspergillosis [CNPA])
Aspergilloma
Invasive aspergillosis
However, in patients who are severely immunocompromised, Aspergillus may hematogenously disseminate beyond the lung, potentially
causingendophthalmitis, endocarditis, and abscesses in the myocardium, kidney, liver, spleen, soft tissue, and bone. In
addition, Aspergillus is second to Candidaspecies as a cause of fungal endocarditis. Aspergillus -related endocarditis and wound infections
occur in the context of cardiac surgery.
ABPA is a hypersensitivity reaction to A fumigatus colonization of the tracheobronchial tree and occurs in conjunction with asthma and cystic
fibrosis (CF). Allergic fungal sinusitis may also occur alone or with ABPA. Bronchocentric granulomatosis and malt worker's lung are 2
hypersensitivity lung diseases that are caused by Aspergillus species, but they are rare.
An aspergilloma is a fungus ball (mycetoma) that develops in a preexisting cavity in the lung parenchyma. Underlying causes of the cavitary
disease may include treated tuberculosis or other necrotizing infection, sarcoidosis, CF, and emphysematous bullae. The ball of fungus may
move within the cavity but does not invade the cavity wall; however, it may cause hemoptysis.
CNPA is a subacute process usually found in patients with some degree of immunosuppression, most commonly that associated with
underlying lung disease, alcoholism, or long-term corticosteroid therapy. Because it is uncommon, CNPA often remains unrecognized for
weeks or months and can cause a progressive cavitary pulmonary infiltrate.
Invasive aspergillosis is a rapidly progressive, often fatal infection that occurs in patients who are severely immunosuppressed, including
those who are profoundly neutropenic, those who have received bone marrow or solid organ transplants, and patients with advanced
AIDS
[15]
or chronic granulomatous disease. This infectious process is characterized by invasion of blood vessels, resulting in multifocal
infiltrates, which are often wedge-shaped, pleural-based, and cavitary. Dissemination to other organs, particularly the central nervous
system, may occur.
Pathophysiology
Aspergillus causes a spectrum of disease, from colonization to hypersensitivity reactions to chronic necrotizing infections to rapidly
progressive angioinvasion, often resulting in death. Rarely found in individuals who are immunocompetent, invasive Aspergillus infection
almost always occurs in patients who are immunosuppressed by virtue of underlying lung disease, immunosuppressive drug therapy, or
immunodeficiency.
Aspergillus hyphae are histologically distinct from other fungi in that the hyphae have frequent septae, which branch at 45 angles. The
hyphae are best visualized in tissue with silver stains. Although many species of Aspergillus have been isolated in nature, A fumigatus is the
most common cause of infection in humans.A flavus and A niger are less common. Likely, this relates to the ability of A fumigatus, but not
most other Aspergillus species, to grow at normal human body temperature.
Human host defense against the inhaled spores begins with the mucous layer and the ciliary action in the respiratory tract. Macrophages and
neutrophils encompass, engulf, and eradicate the fungus. However, many species ofAspergillus produce toxic metabolites that inhibit
macrophage and neutrophil phagocytosis. Corticosteroids also impair macrophage and neutrophil function. Underlying immunosuppression
(eg, HIV disease, chronic granulomatous disease, pharmacologic immunosuppression) also contributes directly to neutrophil dysfunction or
decreased numbers of neutrophils. In individuals who are immunosuppressed, vascular invasion is much more common and may lead to
infarction, hemorrhage, and necrosis of lung tissue. Persons with CNPA typically have granuloma formation and alveolar consolidation.
Hyphae may be observed within the granulomata.
Frequency
United States
Although allergy to Aspergillus, as manifested by a positive skin test reaction toAspergillus antigen, is present in approximately 25% of
people with asthma and 50% of patients with CF, ABPA is much less common. From surveys and an ABPA registry, 0.25-0.8% of people
with asthma and approximately 7% of patients with CF are estimated to have ABPA. The incidence of ABPA in people with asthma who are
steroid-dependent or have associated central bronchiectasis is higher, estimated at 7-10%.
CNPA is rare. Frequently undetected in life and found at autopsy, the frequency of chronic necrotizing Aspergillus pneumonia may be
underestimated.
The frequency of invasive aspergillosis reflects disease states and treatments that result in prolonged neutropenia and immunosuppression.
Invasive aspergillosis is estimated to occur in 5-13% of recipients of bone marrow transplants, 5-25% of patients who have received heart or
lung transplants, and 10-20% of patients who are receiving intensive chemotherapy for leukemia. Although it has been described in
individuals who are immunocompetent, invasive aspergillosis is exceedingly uncommon in this population.
Aspergilloma is not rare in patients with chronic cavitary lung disease and CF. In one survey of patients with cavitary lung disease due to
tuberculosis, 17% developed aspergilloma.
International
The incidence of ABPA in people with asthma appears to be higher in Great Britain compared with the United States.
Mortality/Morbidity
Invasive aspergillosis is associated with significant mortality, with a rate of 30-95%.
Chronic necrotizing Aspergillus pneumonia has a reported mortality rate of 10-40%, but rates as high as 100% have been noted because it
often remains unrecognized for prolonged periods.
Aspergilloma is associated with hemoptysis, which may be severe and life threatening.
ABPA may cause problems with asthma control. Repeated episodes of ABPA may cause widespread bronchiectasis and resultant chronic
fibrotic lung disease.
Age
The age distribution of aspergillosis is consistent with that of the various comorbid conditions with which it is associated.
Proceed to Clinical Presentation