eMedicine Specialties > Pulmonology > Infectious Lung Diseases

Aspergillosis

Eloise M Harman, MD, Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Florida College of Medicine

Updated: Mar 7, 2008

Introduction

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 Aspergillosis (dermatology focus), Aspergillosis (pediatric focus), and Aspergillosis, Thoracic (radiology focus). A Medscape CME course that may be of interest is New Directions in the Management of Invasive Fungal Infections in Neonatal and Pediatric Populations.

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 4 main syndromes, including allergic bronchopulmonary aspergillosis (ABPA), chronic necrotizing Aspergillus pneumonia (or chronic necrotizing pulmonary aspergillosis [CNPA]), aspergilloma, and 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, and bone. 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. See also Infective Endocarditis, Endocarditis, Fungal, and Endocarditis.

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. Medscape CME courses of interest include New Pulmonary Therapies for Cystic Fibrosis and Improving Quality of Life for Patients With Cystic Fibrosis.

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.

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 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.

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 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.

Clinical

History

The 4 most common manifestations of Aspergillus lung disease (ie, ABPA, CNPA, aspergilloma, and invasive aspergillosis) have quite different clinical manifestations.

• ABPA is a syndrome occurring in asthmatic persons and patients with CF that results from a hypersensitivity reaction to Aspergillus colonization of the tracheobronchial tree. 
  • This syndrome may cause fever and pulmonary infiltrates that are unresponsive to antibacterial therapy.
  • Patients often have a cough and produce mucous plugs, which may form bronchial casts. They may have hemoptysis.
  • People with asthma who have 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.
• 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.
  • In patients with HIV disease, aspergilloma may occur in cystic areas resulting from prior Pneumocystis carinii pneumonia.
  • Of patients with aspergilloma, 40-60% experience hemoptysis, which may be massive and life threatening. Less commonly, aspergilloma may cause cough and fever.
• CNPA manifests as a subacute pneumonia unresponsive to antibiotic therapy, which progresses and cavitates over weeks or months. 
  • Patients with CNPA have underlying disease, such as steroid-dependent chronic obstructive pulmonary disease (COPD) or alcoholism, with symptoms that may include fever, cough, night sweats, and weight loss.
  • Usually, patients have received prolonged courses of antibiotic therapy and sometimes empiric antituberculous therapy without response prior to diagnosis via biopsy or culture.
• Invasive aspergillosis typically manifests with fever, cough, dyspnea, pleuritic chest pain, and, sometimes, hemoptysis in patients with prolonged neutropenia or immunosuppression.
  • For patients at risk for Aspergillus infection after organ transplantation, the most common transplant type at risk is bone marrow. However, invasive aspergillosis may be observed in patients who have received lung, heart, and other solid organ transplants. Of these solid organ transplants, lung transplant recipients are at significant risk. After bone marrow transplantation, invasive aspergillosis has a bimodal distribution, occurring early with prolonged neutropenia before engraftment and later in the context of high-dose corticosteroid therapy for graft versus host disease.
  • In patients with leukemia and lymphoma, aspergillosis may occur after chemotherapy-induced bone marrow suppression, with resultant prolonged neutropenia, manifesting with persistent fever and pulmonary infiltrates despite broad-spectrum antibiotic therapy. Radiographic and CT scan images may reveal characteristic patterns, including nodules, cavitary infiltrates, and focal infiltrates.

Physical

Physical findings in patients with aspergillosis are nonspecific.

• In ABPA, the patient may have fever. Wheezing may be noted upon auscultation of the chest. The patient may produce mucous plugs upon coughing.
• In invasive aspergillosis and chronic Aspergillus pneumonia, the patient is febrile and may have evidence of lung consolidation. Patients may have hemoptysis. Patients with invasive aspergillosis may be tachypneic and have rapidly progressive worsening hypoxemia.
• In patients with aspergilloma, signs of the underlying lung disease may be noted, including clubbing in patients with CF. Hemoptysis is frequently present.

Causes

Invasive aspergillosis rarely occurs in patients who are immunocompetent.

• ABPA is found in people with asthma and/or CF who are allergic to Aspergillus. The thick mucus found in the airways of these patients may make clearing inhaled Aspergillus spores difficult. Additionally, evidence of genetic susceptibility has been reported. Patients who have certain HLA alleles, particularly HLA-DR2, have increased susceptibility to ABPA, whereas HLA-DQ2 appears to be protective.²
• Risk factors involved in the development of CNPA include underlying pulmonary disease (including COPD, interstitial lung disease, and previous thoracic surgery) and altered immune status due to chronic corticosteroid therapy, alcoholism, collagen-vascular disease, or chronic granulomatous disease.
• Aspergilloma typically develops in the context of preexisting cavitary disease. Aspergillomas may develop in patients with invasive aspergillosis or chronic necrotizing Aspergillus pneumonia.
• Invasive aspergillosis occurs almost exclusively in patients who are immunocompromised.
  • Neutropenia and corticosteroid therapy are major risk factors.
  • In addition to patients who have undergone transplantation, patients profoundly neutropenic after receiving chemotherapy for hematologic malignancies or lymphoma, children with chronic granulomatous disease, and patients with late-stage HIV disease also are at risk.
  • Specific risk factors for invasive aspergillosis after bone marrow transplantation include prolonged neutropenia, graft versus host disease, high-dose corticosteroid therapy, disruption of normal mucosal barriers, mismatched or unrelated donor transplants, and the presence of central venous catheters.
  • Invasive Aspergillus infection in patients without malignancy or prior chemotherapy (who probably are nevertheless not immunocompetent) is most commonly seen in those with critical illness and COPD who are taking long-term corticosteroid therapy.³

Differential Diagnoses

Other Problems to Be Considered

Mucoid impaction
Septic pulmonary emboli

Workup

Laboratory Studies

Because Aspergillus infection may cause colonization, allergy, or invasive infection, its manifestations are quite variable and are best considered based on the disease process.

• ABPA is defined by several abnormalities, including asthma, eosinophilia, a positive skin test result for A fumigatus, marked elevation of the serum immunoglobulin E (IgE) level to greater than 1000 IU/dL, fleeting pulmonary infiltrates, central bronchiectasis, mucoid impaction, and positive test results for Aspergillus precipitins (primarily immunoglobulin G [IgG], but also immunoglobulin A and immunoglobulin M, antibodies). Minor criteria for diagnosis include positive Aspergillus radioallergosorbent assay test results and culture findings for Aspergillus in sputum.
• Diagnostic criteria for ABPA in persons with CF were recently revised by the Cystic Fibrosis Foundation. ABPA is considered a definite diagnosis requiring treatment if the following are noted: (1) clinical deterioration, including cough, wheeze, increased sputum production, diminished exercise tolerance, or diminished pulmonary function; (2) total serum IgE level greater than 1000 IU/mL or a greater than 2-fold rise from baseline; (3) positive serology results for Aspergillus (Aspergillus precipitins or Aspergillus -specific IgG or IgE); and (4) new infiltrates on chest radiographs or CT scans. Treatment for ABPA is also recommended in patients with CF who have new radiographic findings and symptoms and a change in baseline IgE level to greater than 500 IU/mL.⁴
• Definitive diagnosis of invasive aspergillosis or chronic necrotizing Aspergillus pneumonia depends on the demonstration of the organism in tissue.
  • In the appropriate clinical setting of pulmonary infiltrates in a patient who is neutropenic or immunosuppressed, visualization of the characteristic fungi using Gomori methenamine silver stain or Calcofluor or a positive culture result from sputum, needle biopsy, or bronchoalveolar lavage (BAL) fluid should result in the prompt institution of therapy. This is especially important after bone marrow transplantation because a positive Aspergillus culture result from sputum has a 95% positive predictive value for invasive disease. However, a negative fungus result from culture of sputum or BAL fluid does not exclude pulmonary aspergillosis because Aspergillus is cultured from sputum in 8-34% of patients and from BAL fluid in 45-62% of patients eventually found by biopsy or autopsy to have invasive disease.
  • An assay to detect galactomannan, a major component of the Aspergillus cell wall, is available.⁵ Patients who are at high risk, such as those who have received stem cell transplants or who have prolonged neutropenia, may be screened for the development of invasive Aspergillus infection by monitoring serum galactomannan levels weekly.⁶ The presence of an elevated galactomannan level in BAL fluid may also be helpful in the diagnosis of pulmonary aspergillosis in patients in whom compatible radiographic changes are present and BAL testing is performed in the suspicious area.⁷
• Aspergilloma does not cause many characteristic laboratory abnormalities. Aspergillus precipitin antibody test results (ie, for IgG) are usually positive.

Imaging Studies

• In invasive aspergillosis, 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. CT scan images may be very helpful in the early diagnosis of aspergillosis because they may demonstrate a characteristic halo sign (ie, an area of ground-glass infiltrate surrounding nodular densities).⁸ Later disease 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.
• ABPA may cause variable manifestations, from fleeting pulmonary infiltrates to mucoid impaction to central bronchiectasis. Mucoid impaction of bronchiectatic areas may cause a lobulated infiltrate, which has been likened to a cluster of grapes or a hand in a mitten. 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.
• In aspergilloma, chest radiography reveals 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. The scanning may be performed with the patient in the supine and prone positions to demonstrate movement of the mass within the cavity.

Other Tests

• For ABPA, prick or intradermal skin testing with Aspergillus antigen results in a positive reaction manifested by wheal and flare.

Procedures

• Procedures that may be helpful for the diagnosis of invasive aspergillosis include bronchoscopy, needle biopsy, and open lung biopsy. At bronchoscopy, BAL in areas of pneumonia may provide evidence for the diagnosis. Transbronchial biopsy may be helpful, but it may not be possible because patients are often thrombocytopenic because of bone marrow suppression. Peripheral lesions may be amenable to transthoracic needle aspiration and biopsy. Open lung biopsy through a small thoracotomy or by video-assisted thoracoscopy may be the only way to obtain tissue samples large enough to confirm the presence of Aspergillus organisms in tissue.^7,9
• For ABPA, mucoid impaction of dilated bronchi can cause a masslike appearance, and patients with ABPA sometimes undergo transthoracic needle aspiration in an effort to obtain diagnostic information. ABPA may be observed in association with chronic eosinophilic pneumonia or bronchiolitis obliterans-organizing pneumonia (BOOP), and patients may require transbronchial or open biopsy for diagnosis of unresolving pulmonary infiltrates with or without mucoid impaction. In the proper context, prick or intradermal skin testing to confirm immediate hypersensitivity to Aspergillus should be performed first because a negative skin test result excludes the diagnosis of ABPA.

Histologic Findings

Histopathology and silver staining for persons with invasive aspergillosis demonstrates the characteristic septate hyphae, branching at acute angles, and acute inflammatory infiltrate and tissue necrosis with occasional granulomata and blood vessel invasion. The airways of patients with ABPA contain mucus filled with degenerating eosinophils and typical fungal hyphae. ABPA may occur on a background of chronic eosinophilic pneumonia and bronchiolitis, granulomatous bronchitis, bronchocentric granulomatosis, and, occasionally, BOOP.

Staging

No staging protocol is used for invasive aspergillosis or aspergilloma. ABPA may be progressive, and the following 5 stages have been described¹⁰ :

• Acute disease
• Remission
• Exacerbation or recurrence
• Corticosteroid-dependent asthma
• End-stage fibrosis

Treatment

Medical Care

The treatment of invasive aspergillosis and chronic necrotizing aspergillosis differs significantly from the treatment of ABPA and aspergilloma.

Invasive aspergillosis^11,12  

This is often rapidly progressive and has a high mortality rate; therefore, preventive therapy and rapid institution of therapy in patients in whom invasive aspergillosis is suggested may be lifesaving. Prophylactic antifungal therapy and the use of laminar airflow (LAF) or high-efficiency particulate air (HEPA) filtration of patient rooms in patients who receive bone marrow transplants and other high-risk patients may prevent invasive aspergillosis. In patients with solid organ transplants, especially lung, in whom Aspergillus is cultured from sputum without evidence of pneumonia (colonization), inhaled amphotericin B may be administered.

When high-risk patients develop a compatible clinical picture, empiric treatment for aspergillosis should be initiated as diagnostic testing is undertaken. Voriconazole is now considered the drug of choice for invasive aspergillosis because of better tolerance and improved survival with its use when compared with amphotericin.¹³ Posaconazole, amphotericin B, or amphotericin B lipid formulations may be considered as empiric therapy in critically ill patients if the clinical picture, particularly the presence of sinusitis, could be compatible with mucormycosis, because voriconazole is ineffective for Zygomycetes infection. Caspofungin has also been approved for treatment of invasive aspergillosis in patients who are unable to tolerate or are resistant to other therapies.¹⁴ Initial combination therapy is usually not indicated and should generally be reserved for treatment failures.¹⁵

If possible, the level of immunosuppression should be decreased. For example, patients who are neutropenic may receive growth factors (ie, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor), and patients with certain types of transplants, in which transplanted organ dysfunction will not be life threatening (eg, renal transplant), may have immunosuppressive medications, including corticosteroids, reduced or discontinued.

Combination antifungal therapy is sometimes used for patients whose disease progresses while on single-drug therapy. Concomitant therapy with azole antifungals and amphotericin is controversial because the azole antifungals decrease amphotericin-binding sites and may therefore diminish its effectiveness. Be alert to the possibility of diminished effectiveness of amphotericin in any patient who has received prior treatment with an azole antifungal, including voriconazole, itraconazole, fluconazole, or ketoconazole. Newer antifungal azoles are under study (eg, ravuconazole) and may be available for compassionate use in patients in whom other therapies have failed. Posaconazole, a new triazole, was recently approved by the US Food and Drug Administration.¹⁶

Aspergilloma

Treatment is considered when patients become symptomatic, usually with hemoptysis. Surgical resection is curative but may not be possible in patients with limited pulmonary function. Oral itraconazole may provide partial or complete resolution of aspergillomas in 60% of patients. Successful intracavitary treatment, using CT-guided, percutaneously placed catheters to instill amphotericin alone or in combination with other drugs, including acetylcysteine and aminocaproic acid, has been reported in small numbers of patients.¹⁷

Bronchial artery embolization may be used for life-threatening hemoptysis in patients thought to have insufficient pulmonary reserve 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).¹⁸ Bronchial artery embolization requires a skilled and experienced radiologist because localizing the abnormal vessel(s) may be challenging. Because the anterior spinal arteries may originate from the bronchial vessels, serious neurologic complications, although rare, may occur.

Allergic bronchopulmonary aspergillosis

This is a hypersensitivity reaction that requires treatment with oral corticosteroids. Inhaled steroids are not effective.

Adding oral itraconazole to steroids in patients with recurrent or chronic ABPA may be helpful.^19,20,21,22 This may allow more rapid resolution of infiltrates and symptoms, facilitating steroid tapering or lowering the needed maintenance corticosteroid dosage. In CF patients with ABPA, the concomitant use of itraconazole and inhaled corticosteroids may increase the risk of adrenal insufficiency.

Patients who have associated allergic fungal sinusitis benefit from surgical resection of obstructing nasal polyps and inspissated mucus in addition to corticosteroid therapy. Nasal washes with amphotericin or itraconazole have also been used.

Case reports have described the beneficial use of the anti-IgE monoclonal antibody omalizumab (Xolair) in patients with ABPA.²³

Chronic necrotizing pulmonary aspergillosis

Treatment consists of therapy with voriconazole, or, in some cases, 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. In addition, reduction or elimination of immunosuppression should be attempted, if possible.

Surgical resection may be considered when localized disease fails to respond to antifungal therapy.

Surgical Care

Invasive aspergillosis and CNPA

Surgical resection is a consideration for localized disease that has failed to respond to prolonged antifungal therapy.²⁴ Aspergillomas may occasionally form in areas of necrotizing pneumonia. These necrotic areas may bleed, sometimes massively, necessitating consideration of surgical resection. Patients may be high-risk surgical candidates because of underlying disease, coagulopathy, or thrombocytopenia and limited pulmonary reserve.

Aspergilloma 

Surgical resection may be considered for massive hemoptysis if pulmonary function is sufficient enough for this sort of intervention. Assessment of operative risk necessitates obtaining pulmonary function studies, arterial blood gas determinations, and, possibly, split lung function studies (eg, quantitative perfusion lung scanning). Because aspergilloma occurs in cavitary areas, the affected lung may not be functional. Surgical resection may be difficult because of scarring, pleural adhesion, and the presence of abnormal vasculature.

Allergic bronchopulmonary aspergillosis 

Areas of mucoid impaction may have a masslike appearance and are sometimes resected as an undiagnosed lung mass; however, steroid therapy and oral itraconazole therapy are preferred. Allergic fungal sinusitis usually requires endoscopic sinus surgery to improve drainage.

Consultations

Consultation with a pulmonologist may be helpful for patients suggested to have invasive aspergillosis or chronic necrotizing Aspergillus pneumonia in order to establish a definitive diagnosis. Once the diagnosis is established, consultation with an infectious diseases specialist is usually helpful in management, especially if patients do not respond to initial fungal therapy.

Patients with ABPA or allergic fungal sinusitis should be treated by a pulmonologist or allergist familiar with the management of these conditions. Consultation with a pulmonologist is also indicated in patients with aspergilloma. Input from a thoracic surgeon may also be needed if surgical resection is feasible. In selected patients, consultation with an invasive radiologist may be indicated for CT-directed catheter placement to allow intracavitary therapy or bronchial artery embolization.

Medication

The treatment of invasive aspergillosis and chronic necrotizing aspergillosis requires intravenous antifungal therapy. Voriconazole is usually first-line therapy, sometimes in combination with other agents such as caspofungin. Amphotericin may sometimes be used in treatment failures. ABPA is a hypersensitivity reaction treated with corticosteroids. The addition of oral antifungal therapy with itraconazole is beneficial in the management of ABPA. Aspergillomas may respond to prolonged oral itraconazole therapy. Intracavitary therapy with amphotericin has also been used in small numbers of patients.

Antifungal agents

Mechanism of action may involve increasing the permeability of the cell membrane, which, in turn, causes intracellular components to leak.

Amphotericin B (Abelcet, AmBisome, Amphotec)

Polyene antibiotic produced by a strain of Streptomyces nodosus. Can be fungistatic or fungicidal. Binds to sterols (eg, ergosterol) in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death. Newer lipid formulations are as effective as original formulation and have less nephrotoxicity. May be associated with fever, rigors, and nausea (premedication with hydrocortisone and meperidine may be beneficial). Adequate hydration may decrease nephrotoxicity, and patients who can tolerate fluid should be administered pre- and post-hydration.

Dosing

Adult

Amphotericin: 0.5-1.5 mg/kg/d IV
Abelcet: 5 mg/kg/d IV
Amphotec: 3-4 mg/kg/d IV; as much as 7.5 mg/kg/d IV may be required in severe illness
AmBisome: 3-5 mg/kg/d IV
Inhaled amphotericin for Aspergillus prophylaxis or colonization: 50 mg/d preceded by albuterol

Pediatric

Administer as in adults

Interactions

Antineoplastic agents may enhance potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine, aminoglycosides, cidofovir, cyclosporine, pentamidine, tacrolimus, and vancomycin; previous treatment with azole antifungals may diminish efficacy of amphotericin; may have added nephrotoxicity and myelotoxicity when coadministered with zidovudine; may increase toxicity of flucytosine and enhance activity of daunorubicin and doxorubicin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Severe reactions during infusion not blocked by premedication may preclude use; potential adverse effects include electrolyte abnormalities and anemia; monitor renal function, serum electrolytes (eg, magnesium and potassium), liver function, CBC count, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when interrupted for >7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients who are neutropenic and are receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock

Itraconazole (Sporanox)

Synthetic triazole antifungal agent with greater activity against Aspergillus than fluconazole or ketoconazole. Fungistatic activity. Slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Available in PO formulations (eg, cap, susp) and is useful for prolonged antifungal therapy. IV formulation has recently become available. Because it is insoluble in water, the PO and IV susp are solubilized with hydroxypropyl-beta-cyclodextrin.

Dosing

Adult

Cap: 200-400 mg/d PO with food or cola
Life-threatening infections: 200 mg PO tid for 3 d initially, followed by 200 mg PO bid
PO susp: 200-400 mg/d on empty stomach
IV: 200 mg bid for 2 d, followed by 200 mg/d

Pediatric

Not established
Suggested dose 3-16 years: 5-10 mg/kg/d PO for Aspergillus prophylaxis in children with chronic granulomatous disease (use PO susp)

Interactions

Inhibits hepatic cytochrome P-450, increasing levels of many drugs; serious cardiac toxicity may occur when coadministered with cisapride, dofetilide, pimozide, or quinidine; may interfere with metabolism of some benzodiazepines, resulting in prolonged sedation; coadministration with lovastatin or simvastatin increases risk of rhabdomyolysis; monitor levels of cyclosporine, tacrolimus, and digoxin (itraconazole raises levels and dose adjustment needed); absorption of PO itraconazole requires acidic environment in stomach (H2 blockers and proton pump inhibitors should not be administered concurrently)

Contraindications

Documented hypersensitivity; breastfeeding; renal failure; left ventricular failure

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic insufficiencies; caution in patients with cardiac risk factors (left ventricular dysfunction has been noted)

Caspofungin (Cancidas)

Antifungal with efficacy against A fumigatus, A flavus, and Aspergillus terreus. First of a new class of antifungals called echinocandins. Works on a component of fungal cell walls that is not present in mammalian cells. Indicated for Aspergillus infection in patients who are refractory to or cannot tolerate other therapies. Has not been studied for primary therapy.

Dosing

Adult

70 mg IV loading dose on day 1, followed by 50 mg/d IV; duration depends on response to therapy (averages 1 mo)

Pediatric

Not established

Interactions

Coadministration with cyclosporine may cause transient increases in liver enzyme levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic insufficiencies; adverse effects include fever, complications in infusion vein, headache, nausea, vomiting, rash, and skin flushing

Voriconazole (VFEND)

Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P-450–mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.

Dosing

Adult

Loading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses
Maintenance: 4 mg/kg IV q12h infused over 2 h; when able to tolerate PO, may switch to 200 mg PO q12h
Note: For inadequate response, may increase to 300 mg PO q12h; <40 kg, administer PO maintenance dose of 100 mg PO q12h (may increase to 150 mg PO q12h)

Pediatric

<12 years: Not established
>12 years: Data limited; administer as in adults

Interactions

CYP-450 2C19 (highest affinity), 2C9, and 3A4 (minor) substrate and inhibitor; CYP-450 inducers (eg, rifampin) have been shown to decrease steady-state peak plasma levels by up to 93%; may increase serum levels of drugs metabolized by CYP-450 2C19 or 2C9, of which some are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids); others may require more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG CoA inhibitors, benzodiazepines, calcium channel blockers)

Contraindications

Documented hypersensitivity; do not administer IV form with CrCl <50 mL/min (decreased excretion of IV vehicle); coadministration with rifampin, rifabutin, carbamazepine, barbiturates, sirolimus, pimozide, quinidine, cisapride, or ergot alkaloids

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Decrease maintenance dose with hepatic dysfunction; common adverse effects include visual disturbances, fever, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, rash (including Stevens-Johnson syndrome and phototoxicity), and respiratory disorder; rare cases of severe hepatotoxicity have been reported; administer PO 1 h ac or pc

Posaconazole (Noxafil)

Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

Dosing

Adult

200 mg (5 mL) PO tid with food or liquid nutritional supplement to enhance absorption

Pediatric

<13 years: Not established
>13 years: Administer as in adults

Interactions

Metabolized via UDP glucuronidation; P-gp efflux substrate; CYP3A4 inhibitor; UDP-G inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk); inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers (eg, nifedipine, bepridil), HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin), ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, or vinca alkaloids (eg, vincristine, vinblastine)

Contraindications

Documented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates likely to result in serious toxicities (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver function impairment; caution with preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon provided in package; avoid if breastfeeding

Corticosteroids

Useful in the management of allergic reactions. These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Meticorten, Orasone)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dosing

Adult

0.5-1 mg/kg/d PO for 2 wk; taper over 3-6 mo for management of ABPA or allergic fungal sinusitis

Pediatric

Administer as in adults

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective-tissue infections; fungal or tubercular skin infections; GI bleeding or ulceration

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Follow-up

Further Inpatient Care

For invasive aspergillosis, monitor the patient for resolution of fever, hypoxemia, and pulmonary infiltrates. Patients who do not respond to therapy with voriconazole or combination therapy with voriconazole and caspofungin should be seen in consultation by an infectious disease specialist. Monitoring of serum voriconazole levels may be considered in nonresponders.²⁵ Consider reducing immunosuppression if possible based on the underlying disease. Other considerations include surgical resection for localized disease and the addition of other antifungal agents.

Further Outpatient Care

ABPA is usually managed in an outpatient setting. Serial measurement of the serum IgE level is a useful way to monitor response to therapy and to predict relapse after initial management. Levels are measured every 1-2 months during an exacerbation and every 3 months during remission. The rationale for repeat measurements of IgE levels during clinical remission is that 35% of exacerbations are asymptomatic but may result in lung damage. Elevated IgE levels should be evaluated further with a chest radiograph and institution of therapy with prednisone and possibly itraconazole.

Patients with invasive aspergillosis or CNPA who respond to initial inpatient treatment may require several weeks of antifungal therapy. Oral voriconazole or itraconazole (sometimes chosen because of cost) is administered until clinical and radiographic resolution.

Inpatient & Outpatient Medications

For invasive aspergillosis and CNPA, specific antifungal therapy with oral or intravenous voriconazole is the usual initial therapy. Response to therapy may be poor; in patients who respond, prolonged therapy may be required.

ABPA therapy includes oral prednisone and, in selected cases, oral itraconazole, usually for several months. As the patient is tapered off oral steroids, inhaled corticosteroids should be added for control of underlying asthma. The concomitant use of inhaled budesonide and oral itraconazole has been found to cause adrenal suppression in a significant proportion of patients with CF and ABPA.

For aspergilloma, oral itraconazole therapy may be beneficial. A Japanese study found that 60% of patients with aspergilloma had some response to oral itraconazole. In patients with bilateral aspergillomas or severe underlying disease preventing surgical resection, oral itraconazole therapy may be continued for several months.

Transfer

Transfer to a tertiary care center may be warranted in patients with aspergilloma or invasive aspergillosis with massive hemoptysis if bronchial artery embolization or surgical resection is considered. Patients with invasive aspergillosis who do not respond to initial antifungal therapy may also benefit from transfer to a center where infectious disease expertise in the management of fungal infections is available.

Deterrence/Prevention

Invasive aspergillosis is frequently fatal, and prevention is the best way to decrease its associated morbidity and mortality. The use of LAF rooms or HEPA filters decreases the concentration of fungi and bacteria in hospital rooms. Use of LAF rooms has been shown to decrease the incidence of invasive Aspergillus infection in patients undergoing bone marrow transplantation.

Prophylactic antifungal therapy is also indicated in high-risk patients, as follows:

• Although fluconazole is not effective against Aspergillus, it significantly decreases the incidence of fungal infections after bone marrow transplantation and is the most frequently used oral prophylactic antifungal therapy.²⁶
• Oral itraconazole has been found to be less effective than fluconazole, probably because of poor bioavailability of the drug in capsule form.
• Voriconazole is effective as secondary prophylaxis in patients who have been successfully treated for Aspergillus infection and who again require chemotherapy for consolidation or relapse.²⁷ However, the use of voriconazole may increase the risk of the patient developing zygomycosis.²⁸
• Posaconazole has been shown to be more effective than fluconazole for preventing invasive Aspergillus infection in patients with graft versus host disease, although the overall incidence of fungal infections is similar for both drugs.⁴ Posaconazole is approved for prophylaxis of invasive Aspergillus and Candida infections in high-risk patients, including those with graft versus host disease and prolonged neutropenia from chemotherapy.
• Inhaled amphotericin has also been used for prophylaxis, particularly in lung transplant recipients colonized with Aspergillus.²⁹
• Oral itraconazole appears to be a safe and effective prophylactic antifungal for children with chronic granulomatous disease.

Complications

Invasive aspergillosis may result in respiratory failure and death. Massive hemoptysis may occur. Aspergillus may disseminate to other organs, including the central nervous system, kidneys, and heart, and result in multisystem organ failure.

ABPA may cause atelectasis, asthma exacerbation, and steroid dependence. Recurrent ABPA episodes may result in widespread bronchiectasis and fibrosis.

Hemoptysis is a frequent complication of aspergilloma.

Prognosis

The prognosis for patients with invasive pulmonary aspergillosis is poor. Of these patients, 25-60% may respond to antifungal therapy, but the mortality rate remains high because of the severity of the underlying disease and the need for continued immunosuppressives and steroids in many patients. If patients respond, at least a 50% chance of relapse exists with subsequent courses of immunosuppression. Disease disseminated to the central nervous system carries 100% mortality, as does fungal endocarditis without surgery.

The prognosis for ABPA is fairly good in patients with mildly abnormal pulmonary function. However, patients may remain steroid-dependent. If ABPA is detected late, after the establishment of fibrosis, the response to steroids frequently is poor.

Patient Education

For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

Miscellaneous

Medicolegal Pitfalls

• In patients who are at high risk for aspergillosis (eg, recipients of bone marrow transplant), failure to provide appropriate prophylaxis or to recognize invasive disease and rapidly institute therapy
• In ABPA, failure to recognize ABPA and appropriately monitor patients to prevent the occurrence of widespread fibrosis

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Keywords

aspergillosis, fungus, fungal infection, inhalational fungal disease, mold infection, invasive pulmonary aspergillosis, allergic bronchopulmonary aspergillosis, ABPA, chronic necrotizing pulmonary aspergillosis, CNPA, chronic necrotizing Aspergillus pneumonia, aspergilloma, mycetoma, fungus ball, disseminated aspergillosis, fungal endocarditis, Aspergillus fumigatus, A fumigatus, Aspergillus niger, A niger, Aspergillus flavus, A flavus, Aspergillus clavatus, A clavatus, bronchocentric granulomatosis, malt worker's lung

Contributor Information and Disclosures

Author

Eloise M Harman, MD, Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Florida College of Medicine
Eloise M Harman, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American Medical Women's Association, American Thoracic Society, Phi Beta Kappa, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Om Prakash Sharma, MD, FRCP, FCCP, DTM&H, Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Southern California Keck School of Medicine
Om Prakash Sharma, MD, FRCP, FCCP, DTM&H is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Osler Society, American Thoracic Society, New York Academy of Medicine, and Royal Society of Medicine
Disclosure: Keck School of Medicine, USC None None

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA
Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society
Disclosure: Nothing to disclose.

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