WORKUP

Lab 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.

• 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 does not exclude pulmonary aspergillosis because Aspergillus is cultured from sputum in 8-34% of patients and from BAL in 45-62% of patients eventually found by biopsy or autopsy to have invasive disease.

     

  • Currently available antibody testing is not helpful for the diagnosis of invasive aspergillosis because test results for Aspergillus precipitins are frequently negative in these patients. Serum and urine tests to help detect Aspergillus antigens (galactomannan) are under study and may soon be available to assist in early detection.

• 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. 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 radiograph 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:

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

Procedures:

• Invasive aspergillosis: Procedures that may be helpful for diagnosis include bronchoscopy, needle biopsy, and open lung biopsy. At bronchoscopy, BAL in areas of pneumonia may provide evidence for the diagnosis. Transbronchial biopsy is often helpful but 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.

• 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.

Staging:

• No staging protocol is used for invasive aspergillosis or aspergilloma.

• ABPA may be progressive, and the following 5 stages have been described:

• 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

• 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 air flow (LAF) or high-efficiency particulate air (HEPA) filtration of patient rooms in patients who receive bone marrow transplant and other high-risk patients may prevent invasive aspergillosis.

   

• In patients with solid organ transplants (particularly lung), in whom Aspergillus is cultured from sputum without evidence of pneumonia (colonization), inhaled amphotericin B may be administered. However, when high-risk patients develop a compatible clinical picture, empiric treatment with amphotericin B is indicated as diagnostic testing is undertaken. Amphotericin B lipid formulations should be considered in patients with renal insufficiency.

   

• 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 transplant, 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 sometimes may be used, or newer antifungal agents, such as caspofungin or itraconazole, may be instituted as monotherapy in patients in whom initial therapy with amphotericin B has failed. Concomitant therapy with itraconazole 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 itraconazole, fluconazole, or ketoconazole. Newer antifungal azoles are under study, including voriconazole, posaconazole, and ravuconazole, and may be available for compassionate use in patients in whom other therapies have failed.

• 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.

   

• 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 cystic fibrosis in whom hemoptysis may be related to underlying bronchiectasis with or without aspergilloma). 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.

     

  • Recent studies have also demonstrated a potential benefit from the addition of oral itraconazole to steroids. This may allow more rapid resolution of infiltrates and symptoms, facilitating steroid tapering or lowering the needed maintenance corticosteroid dosage.

     

  • Patients who have associated allergic fungal sinusitis benefit from surgical resection of obstructing nasal polyps and inspissated mucus in addition to corticosteroid therapy.

• Chronic necrotizing Aspergillus pneumonia

   

  • Treatment consists of amphotericin B or amphotericin lipid formulations followed by prolonged oral itraconazole therapy.

     

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

Surgical Care:

• Invasive aspergillosis and chronic necrotizing aspergillosis

• Surgical resection is a consideration for localized disease that has failed to respond to prolonged antifungal therapy.

• 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. Amphotericin is usually first-line therapy, with newer azole antifungals and caspofungin used for amphotericin failures or prolonged therapy. 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.

Drug Category: Antifungal agents -- Mechanism of action may involve increasing the permeability of the cell membrane, which, in turn, causes intracellular components to leak.

Drug Name	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.
Adult Dose	Amphotericin: 0.5-1.5 mg/kg/d Abelcet: 5 mg/kg/d Amphotec: 3-4 mg/kg/d; as much as 7.5 mg/kg/d may be required in severe illness AmBisome: 3-5 mg/kg/d Inhaled amphotericin for Aspergillus prophylaxis or colonization: 50 mg/d preceded by albuterol
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
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
Pregnancy	B - Usually safe but benefits must outweigh the risks.
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

Drug Name	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.
Adult Dose	Cap: 200-400 mg/d with food or cola Life-threatening infections: 200 mg PO tid for 3 d initially, followed by 200 mg bid PO susp: 200-400 mg/d on an empty stomach IV: 200 mg bid for 2 d, followed by 200 mg/d
Pediatric Dose	Not established Suggested dose 3-16 years: 5-10 mg/kg/d for Aspergillus prophylaxis in children with chronic granulomatous disease (use PO susp)
Contraindications	Documented hypersensitivity; breastfeeding; renal failure; left ventricular failure
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)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic insufficiencies; caution in patients with cardiac risk factors (left ventricular dysfunction has been noted)

Drug Name	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 to treat Aspergillus infection in patients who are refractory to or cannot tolerate other therapies. Has not been studied for primary therapy.
Adult Dose	70 mg IV loading dose on day 1, followed by 50 mg/d IV; duration depends on response to therapy (averages 1 mo)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cyclosporine may cause transient increases in liver enzymes
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic insufficiencies; adverse effects include fever, complications in infusion vein, headache, nausea, vomiting, rash, and skin flushing

Drug Name	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.
Adult Dose	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 Dose	<12 years: Not established >12 years: Limited data exist, administer as in adults
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
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)
Pregnancy	D - Unsafe in pregnancy
Precautions	Decrease maintenance dose with hepatic dysfunction; common adverse effects include visual disturbances, fever, rash, 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

 

Drug Category: 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.

FOLLOW-UP

Further Inpatient Care:

• Invasive aspergillosis: Monitor patient for resolution of fever, hypoxemia, and pulmonary infiltrates. Patients who do not respond to therapy with amphotericin B should be treated through consultation with an infectious disease specialist; consider institution of other antifungal agents in combination or sequentially. Oral itraconazole may be used to complete therapy after an initial response to amphotericin. Immunosuppression should be diminished acutely, if possible, and reinstitution will depend upon the initial response and the effect on the underlying disease.

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 itraconazole or alternate-day intravenous amphotericin is administered until clinical and radiographic resolution.

• ABPA diagnosis and management is usually in an outpatient setting.

In/Out Patient Meds:

• Invasive aspergillosis and CNPA: Specific antifungal therapy with intravenous amphotericin B is the usual initial therapy. Amphotericin lipid formulations are used for patients with renal insufficiency. Response to therapy is often poor. However, in patients who respond, prolonged therapy may be required. Itraconazole may be used because it is available in oral capsules and suspension.

• ABPA: Therapy includes oral prednisone and oral itraconazole, usually for several months. As the patient is tapered off oral steroids, inhaled corticosteroids should be added for control of underlying asthma.

• Aspergilloma: Oral itraconazole therapy may be beneficial in patients with aspergilloma. 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 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. Although fluconazole is not effective against Aspergillus, it significantly decreases the incidence of fungal infections after bone marrow transplant and is the most frequently used oral prophylactic antifungal therapy. Oral itraconazole has been found to be less effective than fluconazole, probably because of poor bioavailability of the drug in capsule form. Some studies have found that oral itraconazole solution is effective prophylaxis for invasive fungal infections, but larger studies are needed. In units where increased risk of resistant Candida species or Aspergillus exists, low-dose intravenous amphotericin B (0.1 mg/kg/d) may be used. Inhaled amphotericin has also been used for prophylaxis, particularly in lung transplant recipients colonized with Aspergillus.

• 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 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.

MISCELLANEOUS

Medical/Legal 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