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Aspergillosis

  • Author: Eloise M Harman, MD; Chief Editor: Ryland P Byrd, Jr, MD  more...
 
Updated: Apr 01, 2015
 

Practice Essentials

Aspergillus primarily affects the lungs, causing the following four main syndromes:

  • Allergic bronchopulmonary aspergillosis (ABPA)
  • Chronic necrotizing Aspergillus pneumonia (also termed chronic necrotizing pulmonary aspergillosis [CNPA])
  • Aspergilloma
  • 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 invasive Aspergillus 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 jiroveci pneumonia in patients with HIV infection
  • 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 chronic obstructive pulmonary disease [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 Aspergillus 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. Computed tomography (CT) is helpful for better defining bronchiectasis, and images may demonstrate 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 higher than 1000 IU/mL or a greater than twofold 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 scans provide better definition of the mass within a cavity and may demonstrate multiple aspergillomas in areas of extensive cavitary disease; CT 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 the Aspergillus 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 employed

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.

Next

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 by Aspergillus 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. (See also 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 four 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 causing endophthalmitis, endocarditis, and abscesses in the myocardium, kidney, liver, spleen, soft tissue, central nervous system (CNS), and bone. In addition, Aspergillus is second to Candida species 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 two 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 CNS, may occur.

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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. This difference in frequency is probably related 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 of Aspergillus 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.

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Frequency

United States

Although allergy to Aspergillus, as manifested by a positive skin test reaction to Aspergillus 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 among people with asthma appears to be higher in Great Britain than in the United States.

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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.

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Contributor Information and Disclosures
Author

Eloise M Harman, MD Staff Physician and MICU Director, Pulmonary Division, Gainesville Veterans Affairs Medical Center

Eloise M Harman, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American Medical Womens Association, American Thoracic Society, Phi Beta Kappa, Sigma Xi

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Ryland P Byrd, Jr, MD Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Ryland P Byrd, Jr, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Acknowledgements

Oleh Wasyl Hnatiuk, MD Program Director, National Capital Consortium, Pulmonary and Critical Care, Walter Reed Army Medical Center; Associate Professor, Department of Medicine, Uniformed Services University of Health Sciences

Oleh Wasyl Hnatiuk, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

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