Respiratory Medicine CME
Volume 1, Issue 3 , Pages 205-215, 2008

Aspergillus-related lung disease

Department of Medicine/Pulmonary & Critical Care, New York Methodist Hospital, 506 Sixth Street, Brooklyn, NY 11214, USA

Article Outline

Summary 

Aspergilli are ubiquitous fungi with branched septate hyphae. Aspergillus produces a wide variety of diseases determined by the inoculating dosage, the ability of the host to resist infection at local and systemic levels and the virulence of the organism. These entities differ clinically, radiologically, immunologically, and in their response to various therapeutic agents. Although the fungus can affect any organ system, the respiratory tract is involved in >90% of affected patients. A broad knowledge is required to timely diagnose and aggressively treat the potentially lethal manifestations of Aspergillus-related pulmonary diseases.

 

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Educational Aims: 


•To review the clinical spectrum of Aspergillus-related lung disease.

•To discuss the standardized criteria for the diagnosis of allergic bronchopulmonary aspergillosis.

•To review the factors that predispose to the development of invasive pulmonary aspergillosis.

•To review the latest diagnostic methods used in diagnosis of Aspergillus-related lung disease.

•To discuss recent advances in diagnostic and therapeutic approaches to respiratory diseases caused by Aspergillus.

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Introduction 

Aspergillus is a ubiquitous soil-dwelling organism that is found in humid areas, damp soil or agricultural environments. It is also found on grain, cereal, moldy flour, and organic decay or decomposing matter. Since the first description of aspergillosis in animals by Mayer in 1815 and the first human case of aspergillosis described in 1842 by Bennett,1 more than 350 species that belong to the genus Aspergillus have been described. Only a few are known to be pathogenic in humans such as Aspergillus fumigatus which is responsible for more than 90% of invasive disease,2 followed by A. niger, A. nidulans, A. terreus, A. clavatus, A. flavus, A. niveus, and A. ustus.3 In a recent review of 300 cases with proven IPA, A. terreus was the second most common species, isolated with a frequency of 23%.4

Aspergillus can cause a variety of clinical syndromes ranging from mild, transient asthma to serious, disseminated disease, particularly in the immunosuppressed host. Aspergillus-related pulmonary disorders may be classified into four clinical categories depending on whether the host is atopic, non-atopic or immunosuppressed (see Fig. 1).

This article reviews the clinical spectrum of Aspergillus-related lung disease, highlighting the risk factors, clinical picture, and recent advances in diagnostic and therapeutic approaches.

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Allergic bronchopulmonary aspergillosis (ABPA) 

Allergic bronchopulmonary aspergillosis is a hypersensitivity reaction to Aspergillus antigens, mostly due to A. fumigatus. The incidence of ABPA varies from 6% to 20% of all patients with asthma.5 It occurs with equal frequency in both sexes. Most patients are under age 35years at the time of diagnosis. In patients with cystic fibrosis, the prevalence of ABPA is 0.5–15%.6

The pathogenesis of ABPA is not completely understood. There is no relation between the intensity of exposure to airborne Aspergillus spores and rates of sensitization to the fungus as measured by skin testing.7 Aspergillus-specific IgE-mediated type I hypersensitivity reactions, specific IgG-mediated type III hypersensitivity reactions, and abnormal T-lymphocyte cellular immune responses all appear to play important roles in its pathogenesis.8, 9, 10 ABPA is characterized pathologically by mucoid impaction of the bronchi, eosinophilic pneumonia, and bronchocentric granulomatosis in addition to the histological features of asthma.6 ABPA is usually suspected on clinical grounds, but requires immunological and radiological confirmation in an appropriate clinical setting. The disease manifests itself with low-grade fever, cough, wheezing, brown mucus plugs, and progressive shortness of breath. Pleuritic chest pain and hemoptysis are frequent. Repeated episodes of bronchial obstruction, inflammation, and mucoid impaction can lead to bronchiectasis, fibrosis, and respiratory compromise.6

Chest radiologic findings may show fleeting pulmonary infiltrates in the upper lobes and central in location during acute exacerbations. The radiological signs representing the thickened and inflamed bronchi may be seen on chest radiographs with the development of central bronchiectasis and pulmonary fibrosis at later stages. Computed tomography (CT) findings in allergic bronchopulmonary aspergillosis consist primarily of mucoid impaction and bronchiectasis involving predominantly the segmental and subsegmental bronchi of the upper lobes. In one study, the combination of bronchiectasis with mucous plugging, atelectasis, peripheral airspace consolidation, or ground-glass attenuation (with or without mosaic perfusion or air trapping) enabled radiologists to make a correct diagnosis of ABPA in 84% of cases.11 In approximately 30% of patients, the impacted mucus has high attenuation or demonstrates frank calcification at CT. Differential diagnosis includes other causes of mucoid impaction such as endobronchial lesions, bronchial atresia, and bronchiectasis.

There is no individual test to establish the diagnosis of ABPA.6, 12 Typically, total serum IgE is elevated, and sputum cultures reveal Aspergillus spp. Serum IgE could be used as a marker for flare-ups and responses to therapy.13

Immediate skin test reactivity to A. fumigatus antigens and elevated levels of serum IgG and IgE antibodies to Aspergillus are usually documented.14

Greenberger and Patterson have standardized the criteria for the diagnosis of ABPA (see Fig. 2), not all of which need to be present for the diagnosis to be made.13, 15

A staging system for ABPA has been developed to categorize the differing presentations of ABPA. These stages are not necessarily progressive phases and do not necessarily occur in order.16 Stage I is the acute initial presentation with asthma, markedly elevated IgE level, peripheral eosinophilia, upper and middle lobe infiltrates, and IgE and IgG antibodies to A. fumigatus. In Stage II (remission stage), the IgE falls but usually remains elevated, eosinophilia is absent, and no infiltrates are noted on the chest radiograph. Serum IgG antibodies to Aspergillus antigen may be slightly elevated. Stage III is recurrence with the same findings as in stage I. Stage IV (the corticosteroid-dependent stage) occurs in patients who have asthma in which control of symptoms is dependent on chronic use of high-dose corticosteroid therapy and exacerbations are marked by worsening asthma, radiographic changes, and an increase in IgE level may occur. Frequently, the chest CT scan will show central bronchiectasis. In stage V (fibrotic stage), bronchiectasis and fibrosis develop, and usually lead to irreversible lung disease. The first four are potentially reversible, with no long-term sequelae. The final diagnosis is usually confirmed by use of clinical, radiographic, and immunologic criteria.

Treatment of ABPA aims to control episodes of acute inflammation and to limit progressive lung injury. Glucocorticoids are most commonly used, although there is increasing evidence of benefit from combined therapy with itraconazole. The 2008 Infectious Diseases Society of America guidelines on the treatment of aspergillosis recommend that therapy of ABPA should consist of a combination of glucocorticoids and itraconazole.17 Treatment with corticosteroids leads to relief of bronchospasm, resolution of radiographic infiltrates, and reduction in serum total IgE and peripheral eosinophilia.18, 19 Two weeks of daily therapy of oral prednisone (0.5mg/kg/day), followed by gradual tapering, has been recommended for new ABPA infiltrates.20, 21 Most patients, however, require prolonged low-dose corticosteroid therapy to control their symptoms and minimize relapses.

Itraconazole has been effective in improving symptoms, facilitating weaning from corticosteroids, decreasing Aspergillus titers, and improving radiographic abnormalities and pulmonary function.22 Itraconazole is thought to work by reducing the antigenic stimulus for bronchial inflammation.17 The antifungal effects can be inferred by the ability of itraconazole to reduce specific Aspergillus IgG.23 One study showed that 46% of patients treated with itraconazole (200mg b.i.d. for 16weeks), had a significant response, which was defined as a 50% reduction in the corticosteroid dose, a decrease of at least 25% in the serum IgE concentration, and a 25% improvement in exercise tolerance or pulmonary function test results, or the resolution or absence of pulmonary infiltrates.24 Itraconazole may augment the activity of corticosteroids via inhibition of their metabolism, which may lead to abnormal ACTH stimulation and adrenal insufficiency.25 The usual duration of therapy is 3–6months.6 Total serum IgE serves as a marker of ABPA disease activity, and should be checked 6–8weeks after the initiation of therapy, then every 8weeks for 1year after that to determine a baseline range for each patient.26

Patients may develop clinicopathologic syndromes related to ABPA. The mucoid impaction syndrome may be seen without asthma or other features of the disease. The patient usually presents with a cough and expectoration of mucus plugs. The mucus plugging may lead to atelectasis. In patients presenting with bronchocentric granulomatosis, necrotizing granulomas obstruct and destroy the bronchioles. The Aspergillus hyphae can be identified within the granulomas in up to 50% of patients with bronchocentric granulomatosis.27 The eosinophilic infiltrates and fibrosis are present in the lung parenchyma; however, there is no tissue or vascular invasion by the Aspergillus. Clinically, the patients are almost always asthmatic and have a persistent cough with typical findings of elevated peripheral blood eosinophil count, elevated total serum IgE, and circulating IgE antibodies to Aspergillus species. Sputum gram stain and culture occasionally reveal Aspergillus.28, 29

The chest radiograph usually shows solitary or multiple pulmonary nodules that may be mistaken for malignancies. Aspergillus rarely has been implicated in the etiology of eosinophilic pneumonitis.

The typical presentation of these patients is cough, dyspnea, and fever associated with peripheral pulmonary infiltrates, and an elevation of Aspergillus IgE levels. The diagnosis usually is confirmed by biopsy, and patients respond well to corticosteroid therapy.30, 31

When a patient develops hypersensitivity granulomatous inflammation of the distal airways and lung parenchyma, it is called extrinsic allergic alveolitis, also known as, hypersensitivity pneumonitis. This is related to intense or recurring inhalation of various antigens, including thermophilic bacteria, fungi, bird excreta, and chemical agents.

The acute form of the disease presents within hours of exposure to the antigens with dyspnea, cough, fever, and myalgia. In advanced cases, there may be features of right-sided heart failure. The chest radiograph usually shows interstitial and alveolar nodular infiltrates. In the chronic stage, a reticulo-interstitial pattern and honeycombing may be seen. Serum levels of IgG antibodies to Aspergillus are elevated when the disease is due to Aspergillus.32

The management of the acute form of hypersensitivity pneumonitis includes avoiding further exposure to the offending agents and corticosteroid therapy.33, 34

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IPA 

Invasive pulmonary aspergillosis (IPA) is characterized by proliferation of fungal mycelia in the pulmonary parenchyma. This disease is due to tissue invasion with the fungi. It is uncommon and occurs primarily in the setting of immunosuppression. There have been less than 20 cases reported in healthy patients. Invasion of the pulmonary vasculature may result in hemorrhagic infarction. Factors that predispose to the development of invasive aspergillosis include neutropenia, hematopoietic stem-cell and solid organ transplantation, prolonged and high-dose corticosteroid therapy, hematological malignancy, cytotoxic therapy, advanced AIDS, and chronic granulomatous disease. The risk factors are summarized in (see Fig. 3).

Neutropenia is the most important risk factor, and it is estimated that IPA accounts for 7.5% of all infections in neutropenic patients following induction therapy for acute myelogenous leukemia.35 The risk of IPA in these patients is increased with the duration of neutropenia and is estimated to be 1% per day for the first 3weeks, after which time it increases to 4% per day. The epidemiology of IPA is changing and now less than one-third of all patients diagnosed with IPA are neutropenic at the time of diagnosis.36 Another significant risk factor for IPA is solid organ transplantation, especially after lung and hematopoietic stem-cell transplant. It is estimated that 5% of BMT recipients develop IPA with mortality rates ranging between 30% and 80%.36, 37, 38 The mortality rate of IPA exceeds 90% in hematopoietic stem-cell transplantation recipients.39, 40 IPA also has been reported increasingly in patients with HIV infection. The response to therapy is particularly poor in the HIV-infected population.41

Rarely, IPA has been reported in the mildly immunocompromised, such as patients with alcoholism, chronic liver disease, or diabetic ketoacidosis. In a recent review of 545 patients with invasive aspergillosis, BMT was the most frequent risk factor (32%; autologous BMT, 7%; allogeneic BMT, 25%), followed by hematologic malignancy (29%), solid organ transplantation (9%), and AIDS (8%). In 2% of patients, no underlying risk factors were identified.2

The characteristic clinical presentation of invasive aspergillosis is a neutropenic individual who is receiving chemotherapy and having persistent fevers despite treatment with multiple antibiotics. The lower respiratory tract is almost always the primary focus of infection as a result of the inhalation of Aspergillus spores. Patients present with symptoms that are usually non-specific, and consistent with acute bacterial or fungal pneumonia (fever, cough, sputum production, and dyspnea). Other symptoms that are significant and raise the possibility of IPA are pleuritic chest pain (due to vascular invasion leading to small pulmonary infarcts) and hemoptysis that is typically mild but can be massive. IPA is one of the most common causes of hemoptysis in neutropenic patients; and has been reported to be associated with cavitation that occurs with neutrophil recovery.42

With the predilection of Aspergillus to invade blood vessels, IPA commonly leads to areas of infarction and hemorrhage in the primary organ (usually the lungs), and the organism spreads hematogenously to other organs, most commonly the brain and rarely the skin, kidneys, pleura, heart, esophagus, or liver.1 In angioinvasive aspergillosis with vascular dissemination, thrombosis and necrosis are common. The symptoms are intense pleuritic chest pain, sudden dyspnea, tachypnea and hemoptysis.

Aspergillus can cause a bronchitis/tracheobronchitis with severe inflammation of the airways, characterized by ulcers and membrane formation; most often in AIDS patients and lung transplant recipients.1, 43 Hyphae invade the airways and form plugs consisting of mycelia, inflammatory cells, and necrotic debris. These plugs along with the membranes produce airway obstruction resulting in wheezing and dyspnea. Approximately 10% of patients who have invasive aspergillosis develop tracheobronchitis either alone or with pneumonia. Aspergillus sinusitis can occur in patients with HIV infection.44 Pleural effusions or empyemas are rare manifestation of invasive aspergillosis.45, 46

The diagnosis of IPA remains challenging, and the clinician must maintain a high index of suspicion for invasive aspergillosis in patients with risk factors. Definitive diagnosis of invasive aspergillosis is best made by demonstrating the characteristic branching septate hyphae in a lung tissue sample along with a culture that is positive for Aspergillus from the same site. Histopathological diagnosis, by examining lung tissue obtained by thoracoscopic or open-lung biopsy, remains the“gold standardr“ in the diagnosis of IPA.47

Histopathological examination also allows for the exclusion of other diagnoses, such as malignancy or non-fungal infectious diseases. Other fungi such as Fusarium and Scedosporium may have comparable appearances, highlighting the importance of performing a culture for the precise identification of the fungus.

The significance of isolating Aspergillus spp. in sputum samples depends on the immune status of the patient. In one study of elderly hospitalized patients with Aspergillus isolated from the sputum, 92% were consistent with colonization, and only 4.5% had IPA.48 In the immunocompromised host sputum culture positivity may be the only indication of IPA. In immunocompetent patients, isolation of Aspergillus spp. from the sputum almost always represents colonization with no clinical consequences and antifungal therapy is generally not indicated. Some studies have shown that sputum samples that are positive for Aspergillus in patients with leukemia or in those who have undergone BMT have a positive predictive value of 80–90%.49, 50, 51

Alternatively, negative sputum samples do not rule out IPA, and it has been shown that negative sputum studies have been found in 70% of patients with established IPA.49, 52 Blood cultures rarely have positive results.53

The chest X-ray may be normal or reveal nodular lesions, patchy infiltrates, or cavitary lesions.54, 55 In one large series of patients, only 10% had a normal chest X-ray.2 The chest CT scan, especially with high-resolution images, is a much more helpful tool in detecting early changes that are not present on chest radiographs. The use of high-resolution chest CT scans in patients with suspected IPA has been associated with better outcomes, most likely due to earlier diagnosis. Patterson et al showed that 85% of chest CT scans had findings suggestive of IPA.2 Bronchoscopy and/or high resolution CT were performed in a study of 33 patients.56 The sensitivity of bronchoalveolar lavage (BAL) fluid and washings were 33% and 50% respectively. CT signs of fungal infection were found in 16 (84%) of 19 episodes. The characteristic CT scan findings are multiple nodules and the halo sign (which is an early radiologic sign that appears as a zone of low attenuation due to hemorrhage surrounding the pulmonary nodule) which is primarily seen in neutropenic patients early in the course of disease. Another late radiological sign is the air crescent sign, which is a crescent-shaped lucency in the region of the original nodule secondary to necrosis.57, 58 In spite of the above referenced findings, neither sign is sensitive. The halo sign may be found as a result of metastasis, bronchoalveolar carcinoma, bronchiolitis obliterans organizing pneumonia, eosinophilic pneumonia, or other fungal infection.59

Fungal smear and culture of BAL fluid is helpful in the diagnosis of IPA, particularly in patients with diffuse lung involvement. The BAL fluid has high specificity attaining 97%,60 but has low sensitivity. The transbronchial biopsies do not improve the overall diagnostic yield and are associated with increased risks.61 Bronchoscopy may also be useful in detecting Aspergillus antigens in the BAL fluid, and excluding other infections.

Open or thoracoscopic lung biopsies are generally the best way to diagnose pulmonary problems in immunocompromised patients, but even this procedure is associated with approximately 20% false-negative results.62 When BAL and bronchoscopic biopsy are negative, and a high clinical suspicion of invasive aspergillosis persists, an open lung biopsy should be performed.

The poor candidacy of many patients with suspected invasive aspergillosis for surgical or other diagnostic procedures has prompted interest in non-invasive ways for diagnosis. Galactomannan is a cell wall glycoprotein that is released by Aspergillus during growth. The Food and Drug Administration recently approved a double-sandwich ELISA for the detection of galactomannan in serum for the diagnosis of IPA. Serum galactomannan can be detected several days before the presence of clinical signs, an abnormal chest radiograph, or positive culture. The galactomannan enzyme immunoassay (EIA) demonstrates proven reliability in patients with hematologic malignancy; however, the reported sensitivity varies from 44% to 90%.63, 64 False-positive results have been reported in patients receiving β-lactam antibiotics or in those infected with the dimorphic fungi Histoplasma capsulatum or Blastomyces dermatitidis.65 Polymerase chain reaction (PCR) has also been evaluated and appears promising as a potential diagnostic modality, but PCR is not yet commercially available for the diagnosis of Aspergillus,66 and is often associated with false-positive results, because it does not discriminate between colonization and infection.

Detection of serum (1→3)-β-d-glucan, a fungal cell wall constituent, has recently received FDA approval, and is a highly sensitive and specific test for invasive deep mycosis, including candidiasis, fusariosis, and aspergillosis, that could be useful in immunocompromised patients.67 Unfortunately, the presence of (1→3)-β-d-glucan is not specific for Aspergillus but is indicative of invasive fungal infection with several possible fungal pathogens.68 The utility of this assay in non-neutropenic and in allogeneic HSCT recipients at high risk for IPA is not yet known. Patients with severe immunosuppression, particularly after BMT have a poor response to therapy compared to less severely immunosuppressed patients (28% vs. 51%, correspondingly).2 Also, the response is better when IPA was limited to the lung as opposed to patients with disseminated infection (40% vs. 18%, respectively).2

When a high suspicion of IPA exists empiric therapy should be started, especially in immunocompromised patients. Most deaths due to IPA occur during the first 6weeks after the start of therapy.17, 69

Three classes of antifungal agents are available for the treatment of aspergillosis: polyenes, azoles, and echinocandins. Historically, amphotericin B has been the major antifungal drug used in patients with invasive aspergillosis; however, voriconazole is now generally considered the drug of choice for the treatment of invasive aspergillosis and was recommended for this indication by the 2008 Infectious Diseases Society of America guidelines on the treatment of aspergillosis.17, 70, 71

A study which compared voriconazole to amphotericin B as the primary therapy for IPA showed that voriconazole had almost 20% higher response rate and a higher survival at week 12.72 These findings suggest that voriconazole is superior to standard amphotericin B in patients with invasive aspergillosis. Voriconazole has a milder side-effect profile, and is much better tolerated than amphotericin B, but has a significant number of drug-to-drug interactions.73 If the diagnosis of invasive aspergillosis has not been made, and the patient is at high risk of zygomycosis, voriconazole is not recommended because it does not have activity against the zygomycetes.

Itraconazole is considered a second-line agent for the treatment of aspergillosis and is rarely used in immunosuppressed patients with invasive disease. Voriconazole has greater intrinsic activity against Aspergillus species, and both the intravenous and the oral forms are better tolerated than itraconazole. The variable bioavailability and potential toxicities of itraconazole limit its use in patients with invasive disease, and the IV formulation has only limited data to support its use. In a large nonrandomized study itraconazole resulted in complete or partial response in 39% and in a failure to respond to treatment in 26% of patients with IPA. The results were particularly poor in allogeneic BMT recipients and AIDS patients.74 For allergic syndromes and in less invasive disease, itraconazole remains a useful alternative.

One of the newest triazoles, posaconazole, is similar in structure to itraconazole. It is well tolerated, but steady-state levels are not obtained for up to 1week, potentially decreasing its efficacy as primary therapy. Nevertheless, it is effective and safe as salvage therapy in patients with invasive aspergillosis refractory to standard antifungal therapy.75, 76 Long-term use of posaconazole in the treatment of refractory invasive fungal infections appears to be safe; the most common side effects in one study were gastrointestinal in nature.77

The most widely used treatment for invasive aspergillosis is amphotericin-B. The treatment is recommended to continue until the infection appears to be clinically resolved and the immunosuppression improving. The response rate varies greatly from 20% to 83%.78 Lipid based preparations of amphotericin B have been used in an effort to minimize side effects. These preparations enable the infusion of higher doses of amphotericin B with less toxicity and are indicated in patients who are at high risk for nephrotoxicity, or have toxic reactions while receiving amphotericin B.79

The echinocandins (caspofungin, micafungin, and anidulafungin) are a novel class of antifungal agents with a unique mechanism of action. They are effective agents in the treatment of IPA resistant to standard treatment, or if the patient cannot tolerate first-line agents.70, 80 Although all three of the currently available echinocandins have demonstrated activity against Aspergillus, caspofungin is the only one currently approved by the FDA as second-line treatment for invasive aspergillosis. There are no prospective randomized studies that show improved efficacy with combination therapy (rather than single agents) in the management of primary IPA. Combination therapy of an echinocandin with either a lipid formulation of amphotericin B or triazole agent appears promising, but cannot be recommended for the routine treatment of primary IPA. Controlled randomized prospective studies are needed to document the value of this approach.

Surgery can be used to debride necrotic tissue and to remove infected tissue in patients with invasive aspergillosis; however, many neutropenic patients also have profound thrombocytopenia, which may complicate or preclude surgery as a therapeutic option. Surgery should be considered in cases of massive hemoptysis, pulmonary lesions close to the great blood vessels, or immunocompromised patients undergoing resection of residual localized pulmonary lesions.81, 82

There is a possible benefit from adding immunomodulatory agents (colony-stimulating factors) or interferon-gamma to the treatment of neutropenic patients suspected to have IPA. This may decrease the degree of immunosuppression, in addition to the use of antifungals for the treatment of IPA. Colony-stimulating factors stimulate the bone marrow to produce more neutrophils, and have been shown to augment the phagocytic activity of neutrophils against fungi, including Aspergillus spp.83, 84

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Chronic necrotizing pulmonary aspergillosis 

Chronic necrotizing pulmonary aspergillosis (CNPA) is the description applied to cavitary lung disease, chronic respiratory symptoms, and serum precipitating antibodies to Aspergillus spp. Several reports describe direct invasion of Aspergillus into the lung parenchyma, with CNPA thus described as a subacute or non-angioinvasive form.85

Several of these cases, however, report progressive damage to the lung parenchyma without clear evidence of tissue invasion. The term chronic cavitary pulmonary aspergillosis (CCPA) has been applied to the formation and expansion of multiple pulmonary cavities.86 It was found that these patients usually are middle-aged with evidence of generalized immunosuppression in the form of diabetes mellitus, malnutrition, corticosteroid or radiation therapy, collagen vascular diseases or underlying lung diseases.87, 88

These patients usually present with fever, cough, sputum production, and weight loss for several months, but some patients may be asymptomatic.87 Radiologic findings in CNPA progress slowly over months or years and include unilateral or bilateral segmental areas of consolidation with or without cavitation or adjacent pleural thickening, and multiple nodular areas of increased opacity.89, 90

A fungal ball may be seen in nearly one half of the cases.87 Other helpful but non-diagnostic tests include serum IgG antibodies to Aspergillus (positive results in >90% of the patients) and immediate skin reactivity to Aspergillus antigens.91 Confirmation of the diagnosis requires a histological demonstration of tissue invasion by the fungus, and the growth of Aspergillus species on culture. The yield of transbronchial biopsy specimens or percutaneous aspirates is relatively poor, and a thoracoscopic or open-lung biopsy is rarely performed in these patients. Confirmation of the diagnosis is thus difficult, and delayed diagnosis is common, which may contribute to the morbidity and mortality associated with CNPA. The combination of characteristic clinical and radiological findings and either serological results positive for Aspergillus or the isolation of Aspergillus from respiratory samples is highly indicative of CNPA.86

Patients with CNPA respond to systemic antifungal therapy, but this may be a life-long requirement. Amphotericin B was initially used, with favorable results.87, 92

Itraconazole has been used as a maintenance drug, and its slight inhibition of the immune response is deemed to be useful for recovery from chronic pulmonary aspergillosis.92, 93

Recently, voriconazole has emerged as a primary therapy for CNPA, with a complete or partial response seen in 43% of patients, and improvement or stability in 80%.94

Treatment is best evaluated by using multiple variables such as change of weight, energy levels, improvement of symptoms, decreasing levels of inflammatory markers and total serum IgE level, improvement in infiltrates, and a reduction in cavity size.91

Surgery should be reserved for patients with reasonable respiratory reserve and no other treatment options. It may be appropriate for patients with severe hemoptysis if embolization fails. Mortality varies in reports from 10 to 39% when using itraconazole.92

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Aspergilloma 

When Aspergillus colonizes a pre-existing lung cavity, a fungus ball composed of fungal hyphae, inflammatory cells, fibrin, mucus, and tissue debris, may form an aspergilloma (mycetoma). It is generally thought that the presence of Aspergillus in pulmonary cavities reflects saprophytic colonization and not actual tissue invasion. Aspergilloma is the most common and best recognized form of pulmonary involvement due to Aspergillus.

Many cavitary lung diseases are complicated by aspergillomas, including tuberculosis and sarcoidosis (most common), followed by bronchiectasis, bronchial cysts, bullae, ankylosing spondylitis, neoplasms, and pulmonary infection.95, 96, 97

Sometimes these patients are asymptomatic; however, up to 75% of patients present with hemoptysis98 or productive cough, chest pain, dyspnea, fever, weight loss, or clubbing. Life threatening bleeding may occur from bronchial blood vessels, and may be due to local invasion of blood vessels lining the cavity, endotoxins released from the fungus, or mechanical irritation of the exposed vasculature inside the cavity.99, 100, 101 Although aspergillomas are usually single, they may also be present bilaterally.

The diagnosis of pulmonary aspergilloma is usually based on the clinical and radiographic features, combined with serological or microbiologic evidence of Aspergillus spp.

At radiography, mycetomas are characterized by the presence of solid, round or oval masses with a soft-tissue opacity within a lung cavity.102 Typically, the mass is separated from the wall of the cavity by airspace of variable size and shape, resulting in the “crescent” or Monod's sign.103, 104 The aspergilloma usually moves when the patient changes position. Differential diagnosis for the air crescent sign include angioinvasive aspergillosis, echinococcal cyst, tuberculosis, Rasmussen aneurysm in a tuberculous cavity, lung abscess, bronchogenic carcinoma, hematoma, and P. jiroveci pneumonia.90, 102, 105 Aspergillomas are often associated with thickening of the cavity wall and adjacent pleura.106, 107 In such cases, pleural thickening may be the earliest radiographic sign before any visible changes are seen within the cavity. Reversibility of the pleural thickening corresponding to the resolution of intracavitary fungal material has been demonstrated at follow-up radiography and it suggests that the thickening of the cavity wall and pleura is due to a hypersensitivity reaction.106

While chest radiography does not clearly delineate a cavity, CT scanning of the lungs can be used to demonstrate a cavity and any intracavitary structures. Magnetic resonance imaging findings are particularly informative and can be used in cases where better resolution of the pathology is required.108 The natural history of aspergilloma is variable. In the majority of cases, the lesion remains stable, however, in approximately 10% of cases, it may decrease in size or resolve spontaneously without treatment.102 Sputum cultures for Aspergillus spp. are positive only in 50% of cases.109

Serum IgG antibodies to Aspergillus are positive in almost every case, but may be negative in patients on corticosteroid therapy.110 Aspergillus antigen has been recovered from the BAL of patients with aspergilloma, but the diagnostic value of this test is variable.22, 111

There is no consensus on the treatment of aspergilloma. Treatment is considered only when patients become symptomatic, usually with hemoptysis. Many treatment strategies such as inhaled, intracavitary, and endobronchial instillations of antifungal agents have been tried and reported in small numbers of patients, without consistent success.112, 113, 114 In patients with massive hemoptysis from aspergilloma, administration of amphotericin B percutaneously guided by CT scan can be effective, with resolution of hemoptysis within a few days.115 The role of intravenously administered amphotericin B is uncertain, and some small studies failed to show a benefit.116

Itraconazole has been used with some reduction in the size of the fungus ball, especially in Europe and Japan, and has been shown to penetrate into the aspergilloma.117 Itraconazole is a useful agent for aspergilloma management, and mainly because of its high tissue penetration an oral form has been used, with radiographic and symptomatic improvement in one half to two-thirds of patients, and occasional patients having a complete response.118, 119, 120 The major limitation of itraconazole is that it works slowly and would not be useful in cases of life-threatening hemoptysis.22

Surgical resection of the cavity and removal of the fungus ball is usually indicated in patients with recurrent hemoptysis. Surgical treatment is associated with relatively high mortality rates up to 23%.121, 122 It is important to risk stratify these patients to determine if they would tolerate surgery.

Bronchial artery embolization should be considered as a temporary measure in life threatening hemoptysis or in patients who are not surgical candidates; but hemoptysis usually recurs due to the presence of massive collateral blood vessels.123 The role of newer antifungal azoles such as voriconazole in the treatment of aspergilloma has yet to be determined.

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Conflict of interest statement 

None of the authors have a conflict of interest to declare in relation to this work.

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CME Section 

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Educational questions 

Answer the following questions: 


1.Which of the following statements is true regarding Aspergillus, please select the following statements:
a.Aspergillus fumigatus is responsible for less than 80% of invasive disease.

b.Aspergillus terreus is known to be pathogenic only in animals.

c.Aspergillus is a ubiquitous organism found in cereal, grain, decomposing matter

d.Only 100 species were identified belonging to genus Aspergillus so far

e.Aspergillus can cause a variety of clinical syndromes



I.a, b, c, d True

II.All False

III.c, e True

IV.All True

V.c, d True


2.Which of the following statement regarding allergic bronchopulmonary aspergillosis are correct:
a.It occurs with equal frequency in both sexes.

b.Allergic bronchopulmonary aspergillosis is a hypersensitivity reaction to Aspergillus antigens.

c.In patients with cystic fibrosis, the prevalence of ABPA is up to 15%.

d.There is no relation between the intensity of exposure to airborne Aspergillus spores and rates of sensitization to the fungus as measured by skin testing.

e.The symptoms are low-grade fever, cough, wheezing, brown mucus plugs, and progressive shortness of breath.



I.a, c, d True

II.All False

III.b, d True

IV.All True

V.a, e True


3.Select all applicable statements describing features of Aspergilloma:
a.Mycetoma is created through invasion and destruction of lung parenchyma.

b.Hemoptysis is most common presenting sign.

c.Air crescent sign on radiography.

d.Magnetic resonance imaging can be used in cases where better resolution of the pathology is required.

e.Treatment should be started when patients are asymptomatic.

f.Surgical treatment is associated with mortality of 60%.



I.a, b, c, d True

II.b, c, d True

III.c, d True

IV.All True

V.All False


4.Choose the correct statements regarding chronic necrotizing pulmonary aspergillosis:
a.Confirmation of the diagnosis requires a histological demonstration of tissue invasion by the fungus, and the growth of Aspergillus species on culture.

b.Diabetes mellitus, malnutrition, corticosteroid and radiation therapy are not implemented as risk factors for development of chronic necrotizing pulmonary aspergillosis.

c.Surgery should be the first treatment option for patients diagnosed with chronic necrotizing pulmonary aspergillosis.

d.Radiologic findings in CNPA include only unilateral areas of consolidation and without cavitation.

e.Patients with CNPA do not respond to systemic antifungal therapy.



I.a True

II.a, b True

III.b, d True

IV.c, d True

V.All False


5.Identify the correct statements regarding invasive pulmonary aspergillosis:
a.The lower respiratory tract is almost always the primary focus of infection as a result of the inhalation of Aspergillus spores.

b.Very rarely IPA has been reported in healthy patients.

c.Neutropenia, hematopoietic stem-cell and solid organ transplantation, hematological malignancy, cytotoxic therapy, advanced AIDS are the factors that predispose to the development of invasive aspergillosis.

d.The mortality rate of IPA exceeds 90% in hematopoietic stem-cell transplantation recipients.

e.Voriconazole is now generally considered the drug of choice for the treatment of invasive aspergillosis



I.a True

II.a, b True

III.b, d True

IV.All True

V.All False

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References 

  1. Denning David W. Invasive aspergillosis. Clin Infect Dis. 1998;26:781–805
  2. Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis: disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group. Medicine. 2000;79:250–260
  3. Kradin RL, Mark EJ. The Pathology of Pulmonary Disorders Due to Aspergillus spp. Arch Pathol Lab Med. 2008;132:606–614
  4. Hachem RY, Kontoyiannis DP, Boktour MR, et al. Aspergillus terreus: an emerging amphotericin B-resistant opportunistic mold in patients with hematologic malignancies. Cancer. 2004;101:1594–1600
  5. Slavin R, Stanczyak D, Lonigro A, Broun G. Allergic bronchopulmonary aspergillosis: a North American rarity. Am J Med. 1969;47:306–308
  6. Stevens DA, Moss RB, Kurup VP, et al. Allergic bronchopulmonary aspergillosis in cystic fibrosis—state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis. 2003 Oct 1;37(Suppl. 3):S225–S264
  7. Beaumont F, Kauffman HF, de Monchy JG, Sluiter HJ, de Vries K. Volumetric aerobiological survey of conidial fungi in the North-East Netherlands. II. Comparison of aerobiological data and skin tests with mould extracts in an asthmatic population. Allergy. 1985;40(3):181–186
  8. Cockrill BA, Hales CA. Allergic bronchopulmonary aspergillosis. Annu Rev Med. 1999;50:303–316
  9. Knutsen AP, Slavin RG. In vitro T cell responses in patients with cystic fibrosis and allergic bronchopulmonary aspergillosis. J Lab Clin Med. 1989;113:428–435
  10. Chauhan B, Santiago L, Kirschmann DA, et al. The association of HLA-DR alleles and T cell activation with allergic bronchopulmonary aspergillosis. J Immunol. 1997;159:4072–4076
  11. Johkoh T, Muller NL, Akira M, et al. Eosinophilic lung diseases: diagnostic accuracy of thin-section CT in 111 patients. Radiology. 2000;216(3):773–780
  12. Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 2002;110(5):685–692
  13. Greenberger PA, Patterson R. Diagnosis and management of allergic bronchopulmonary aspergillosis. Ann Allergy. 1986;56:444–448
  14. Wang JL, Patterson R, Rosenberg M, Roberts M, Cooper BJ. Serum IgE and IgG antibody activity against Aspergillus fumigatus as a diagnostic aid in allergic bronchopulmonary aspergillosis. Am Rev Respir Dis. 1978;117:917–927
  15. Rosenberg M, Patterson R, Mintzer R, Cooper BJ, Roberts M, Harris KE. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med. 1977;86:405–414
  16. Patterson R, Greenberger PA, Radin RC, Roberts M. Allergic bronchopulmonary aspergillosis: staging as an aid to management. Ann Intern Med. 1982;96:286–291
  17. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327–360
  18. Rosenberg M, Patterson R, Roberts M, Wang J. The assessment of immunologic and clinical changes occurring during corticosteroid therapy for allergic bronchopulmonary aspergillosis. Am J Med. 1978;64:599–606
  19. Wang JL, Patterson R, Roberts M, Ghory AC. The management of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis. 1979;120:87–92
  20. Capewell S, Chapman BJ, Alexander F, Greening AP, Crompton GK. Corticosteroid treatment and prognosis in pulmonary eosinophilia. Thorax. 1989;44:925–929
  21. Safirstein BH, D'Souza MF, Simon G, Tai EH, Pepys J. Five year follow-up of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis. 1973;108:450–459
  22. Judson MA. Noninvasive Aspergillus pulmonary disease. Semin Respir Crit Care Med. 2004;25:203–219
  23. Wark PA, Hensley MJ, Saltos N, et al. Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: a randomized controlled trial. J Allergy Clin Immunol. 2003;111(5):952–957
  24. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 2000;342:756–762
  25. Skov M, Main KM, Sillesen IB, Muller J, Koch C, Lanng S. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide. Eur Respir J. 2002;20:127–133
  26. Mikita CP, Mikita JA. Allergic bronchopulmonary aspergillosis. Allergy Asthma Proc. 2006;27:82–84
  27. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis. 1990;12:1147–1201
  28. Clee MD, Lamb D, Clark RA. Bronchocentric granulomatosis: a review and thoughts on pathogenesis. Br J Dis Chest. 1983;77(3):227–234
  29. Katzenstein AL, Liebow AA, Friedman PJ. Bronchocentric granulomatosis, mucoid impaction, and hypersensitivity reactions to fungi. Am Rev Respir Dis. 1975;111:497
  30. Warnock ML, Fennessy J, Rippon J. Chronic eosinophilic pneumonia, a manifestation of allergic aspergillosis. Am J Clin Pathol. 1974;62:73–81
  31. Jederlinic PJ, Sicilian L, Gaensler EA. Chronic eosinophilic pneumonia: a report of 19 cases and a review of the literature. Medicine (Baltimore). 1988;67:154–162
  32. Hinojosa M, Fraj J, De La Hoz B, et al. Hypersensitivity pneumonitis in workers exposed to esparto grass (Stipa tenacissima) fibers. J Allergy Clin Immunol. 1996;98:985–991
  33. Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer's lung. Am Rev Respir Dis. 1992;145:3–5
  34. Salvaggio JE. Hypersensitivity pneumonitis. J Allergy Clin Immunol. 1987;79:558–571
  35. Gerson SL, Talbot GH, Hurwitz S, et al. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med. 1984;100:345–351
  36. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis. 1997;175:1459–1466
  37. McWhinney PH, Kibbler CC, Hamon MD, et al. Progress in the diagnosis and management of aspergillosis in bone marrow transplantation: 13 years’ experience. Clin Infect Dis. 1993;17:397–404
  38. Saugier-Veber P, Devergie A, Sulahian A, et al. Epidemiology and diagnosis of invasive pulmonary aspergillosis in bone marrow transplant patients: results of a 5 year retrospective study. Bone Marrow Transplant. 1993;12:121–124
  39. Yeghen T, Kibbler CC, Prentice HG, et al. Management of invasive pulmonary aspergillosis in hematology patients: a review of 87 consecutive cases at a single institution. Clin Infect Dis. 2000;31:859–868
  40. Fukuda T, Boeckh M, Carter RA, et al. Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning. Blood. 2003;102:827–833
  41. Denning DW, Follansbee SE, Scolaro M, et al. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med. 1991;324:654–662
  42. Albelda SM, Talbot GH, Gerson SL, et al. Pulmonary cavitation and massive hemoptysis in invasive pulmonary aspergillosis: influence of bone marrow recovery in patients with acute leukemia. Am Rev Respir Dis. 1985;131:115–120
  43. Nathan SD, Shorr AF, Schmidt ME, Burton NA. Aspergillus and endobronchial abnormalities in lung transplant recipients. Chest. 2000;118:403–407
  44. Mylonakis E, Rich J, Skolnik R, De Orchis D, Flanigan T. Invasive Aspergillus sinusitis in patients with human immunodeficiency virus infection. Report of 2 cases and review. Medicine. 1997;76:249–255
  45. Libshitz HI, Pagani JJ. Aspergillosis and mucormycosis: two types of opportunistic fungal pneumonia. Radiology. 1981;140:301–306
  46. Pagani JJ, Libshitz HI. Opportunistic fungal pneumonias in cancer patients. AJR Am J Roentgenol. 1981;137:1033–1039
  47. Ruhnke M, Bohme A, Buchheidt D, et al. Diagnosis of invasive fungal infections in hematology and oncology—guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol. 2003;82(Suppl. 2):S141–S148
  48. Soubani AO, Khanchandani G, Ahmed HP. Clinical significance of lower respiratory tract Aspergillus culture in elderly hospitalized patients. Eur J Clin Microbiol Infect Dis. 2004;23:491–494
  49. Yu VL, Muder RR, Poorsattar A. Significance of isolation of Aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis: results from a three-year prospective study. Am J Med. 1986;81:249–254
  50. Nalesnik MA, Myerowitz RL, Jenkins R, et al. Significance of Aspergillus species isolated from respiratory secretions in the diagnosis of invasive pulmonary aspergillosis. J Clin Microbiol. 1980;11:370–376
  51. Horvath JA, Dummer S. The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med. 1996;100:171–178
  52. Tang CM, Cohen J. Diagnosing fungal infections in immunocompromised hosts. J Clin Pathol. 1992;45:1–5
  53. Duthie R, Denning DW. Aspergillus fungemia: report of two cases and review. Clin Infect Dis. 1995;20:598–605
  54. Rau WS. Aspergillus infections of the lung: radiological signs. Mycoses. 1997;40(Suppl. 2):25–32
  55. Greene RE, Schlamm HT, Oestmann JW, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis. 2007;44(3):373–379
  56. Von Eiff M, Roos N, Schulten R. Pulmonary aspergillosis: early diagnosis improves survival. Respiration. 1995;62:341–347
  57. Kuhlman JE, Fishman EK, Siegelman SS. Invasive pulmonary aspergillosis in acute leukemia: characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis. Radiology. 1985;157:611–614
  58. Curtis AM, Smith GJ, Ravin CE. Air crescent sign of invasive aspergillosis. Radiology. 1979;133:17–21
  59. Gaeta M, Blandino A, Scribano E, Minutoli F, Volta S, Pandolfo I. Computed tomography halo sign in pulmonary nodules: frequency and diagnostic value. J Thorac Imaging. 1999;14:109–113
  60. Kahn FW, Jones JM, England DM. The role of bronchoalveolar lavage in the diagnosis of invasive pulmonary aspergillosis. Am J Clin Pathol. 1986;86:518–523
  61. Albelda SM, Talbot GH, Gerson SL, et al. Role of fiberoptic bronchoscopy in the diagnosis of invasive pulmonary aspergillosis in patients with acute leukemia. Am J Med. 1984;76:1027–1034
  62. McCabe RE, Brooks RG, Mark JB, et al. Open lung biopsy in patients with acute leukemia. Am J Med. 1985;78:609–616
  63. Herbrecht R, Letscher-Bru V, Oprea C, et al. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol. 2002;20:1898–1906
  64. Maertens J, Verhaegen J, Lagrou K, Van Eldere J, Boogaerts M. Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood. 2001;97:1604–1610
  65. Verweij PE, Mennink-Kersten MA. Issues with galactomannan testing. Med Mycol. 2006;44(Suppl):179–183
  66. Donnelly JP. Polymerase chain reaction for diagnosing invasive aspergillosis: getting closer but still a ways to go. Clin Infect Dis. 2006;42:487–489
  67. Obayashi T, Yoshida M, Mori T, et al. Plasma (1-43)-beta-d-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet. 1995;345:17–20
  68. Odabasi Z, Mattiuzzi G, Estey E, et al. Beta-d-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis. 2004;39:199–205
  69. Wingard JR, Ribaud P, Schlamm HT, Herbrecht R. Changes in causes of death over time after treatment for invasive aspergillosis. Cancer. 2008;112:2309–2312
  70. Spanakis EK, Aperis G, Mylonakis E. New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage. Clin Infect Dis. 2006 Oct 15;43(8):1060–1068
  71. Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med. 2006;173(7):707–717
  72. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408–415
  73. Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis. 2003;36:630–637
  74. Denning DW, Lee JY, Hostetler JS, et al. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am J Med. 1994;97:135–144
  75. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44:2–12
  76. Boutboul F, Alberti C, Leblanc T, et al. Invasive aspergillosis in allogeneic stem cell transplant recipients: increasing antigenemia is associated with progressive disease. Clin Infect Dis. 2002;34:939–943
  77. Raad , Graybill JR, Bustamante AB, et al. Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections. Clin Infect Dis. 2006;42(12):1726–1734
  78. Walsh TJ, Hiemenz JW, Seibel NL, et al. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis. 1998;26:1383–1396
  79. Ng TT, Denning DW. Liposomal amphotericin B (AmBisome) therapy in invasive fungal infections: evaluation of United Kingdom compassionate use data. Arch Intern Med. 1995;155:1093–1098
  80. Cohen-Wolkowiez M, Benjamin DK, Steinbach WJ, Smith PB. Anidulafungin: a new echinocandin for the treatment of fungal infections. Drugs Today (Barc). 2006;42:533–544
  81. Pidhorecky I, Urschel J, Anderson T. Resection of invasive pulmonary aspergillosis in immunocompromised patients. Ann Surg Oncol. 2000;7:312–317
  82. Matt P, Bernet F, Habicht J, et al. Predicting outcome after lung resection for invasive pulmonary aspergillosis in patients with neutropenia. Chest. 2004;126:1783–1788
  83. Giles FJ. Monocyte-macrophages, granulocyte-macrophage colony-stimulating factor, and prolonged survival among patients with acute myeloid leukemia and stem cell transplants. Clin Infect Dis. 1998;26:1282–1289
  84. Roilides E, Sein T, Holmes A, et al. Effects of macrophage colony-stimulating factor on antifungal activity of mononuclear phagocytes against. Aspergillus fumigatus. J Infect Dis. 1995;172:1028–1340
  85. Hope WW, Walsh TJ, Denning DW. The invasive and saprophytic syndromes due to Aspergillus spp. Med Mycol. 2005;43(Suppl 1):S207–S238
  86. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis. 2003;37(Suppl 3):S265–S280
  87. Binder R, Faling J, Pugatch R, et al. Chronic necrotizing pulmonary aspergillosis: a discrete clinical entity. Medicine. 1982;61:109–124
  88. Grahame-Clarke CN, Roberts CM, Empey DW. Chronic necrotizing pulmonary aspergillosis and pulmonary phycomycosis in cystic fibrosis. Respir Med. 1994;88:465–468
  89. Franquet T, Muller NL, Gime´nez A, Domingo P, Plaza V, Bordes R. Semiinvasive pulmonary aspergillosis in chronic obstructive pulmonary disease: radiologic and pathologic findings in nine patients. AJR Am J Roentgenol. 2000;174:51–56
  90. Gefter WB, Weingrad TR, Epstein DM, Ochs RH, Miller WT. Semi-invasive pulmonary aspergillosis. Radiology. 1981;140:313–321
  91. Denning DW. Chronic forms of pulmonary aspergillosis. Clin Microbiol Infect. 2001;7(Suppl 2):25–31
  92. Saraceno JL, Phelps DT, Ferro TJ, Futerfas R, Schwartz DB. Chronic necrotizing pulmonary aspergillosis: approach to management. Chest. 1997;112:541–548
  93. Caras WE, Pluss JL. Chronic necrotizing pulmonary aspergillosis: pathologic outcome after itraconazole therapy. Mayo Clin Proc. 1996;71:25–30
  94. Sambatakou H, Dupont B, Lode H, Denning DW. Voriconazole treatment for subacute invasive and chronic pulmonary aspergillosis. Am J Med. 2006;119:527;e17-24
  95. Kauffman CA. Quandary about treatment of aspergillomas persists. Lancet. 1996;347:1640
  96. Zizzo G, Castriota-Scanderbeg A, Zarrelli N, Nardella G, Daly J, Cammisa M. Pulmonary aspergillosis complicating ankylosing spondylitis. Radiol Med. 1996;91:817–818
  97. Kawamura S, Maesaki S, Tomono K, Tashiro T, Kohno S. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med. 2000;39:209–212
  98. Glimp RA, Bayer AS. Pulmonary aspergilloma. Diagnostic and therapeutic considerations. Arch Intern Med. 1983;143(2):303–308
  99. Tomee JF, van der Werf TS, Latge JP, Koeter GH, Dubois AE, Kauffman HF. Serologic monitoring of disease and treatment in a patient with pulmonary aspergilloma. Am J Respir Crit Care Med. 1995;151:199–204
  100. Addrizzo-Harris DJ, Harkin TJ, McGuinness G, Naidich DP, Rom WN. Pulmonary aspergilloma and AIDS. A comparison of HIV-infected and HIV-negative individuals. Chest. 1997;111:612–618
  101. Aslam PA, Eastridge CE, Hughes FA. Aspergillosis of the lung—an eighteen-year experience. Chest. 1971;59:28–32
  102. Gefter WB. The spectrum of pulmonary aspergillosis. J Thorac Imaging. 1992;7:56–74
  103. Aquino SL, Lee ST, Warnock ML, Gamsu G. Pulmonary aspergillosis: imaging findings with pathologic correlation. AJR Am J Roentgenol. 1994;163:811–815
  104. Logan PM, Muller NL. CT manifestations of pulmonary aspergillosis. Crit Rev Diagn Imaging. 1996;37:1–37
  105. Klein DL, Gamsu G. Thoracic manifestations of aspergillosis. AJR Am J Roentgenol. 1980;134:543–552
  106. Franquet T, Giménez A, Cremades R, Domingo P, Plaza V. Spontaneous reversibility of “pleural thickening” in a patient with semi-invasive pulmonary aspergillosis: radiographic and CT findings. Eur Radiol. 2000;10:722–724
  107. Sanson HE, Baque-Juston M, Wells A, Hansell DM. Lateral cavity wall thickening as an early radiographic sign of mycetoma formation. Eur Radiol. 2000;10:387–390
  108. Fujimoto K, Meno S, Nishimura H, Hayabuchi N, Hayashi A. Aspergilloma within cavitary lung cancer: MR imaging findings. AJR Am J Roentgenol. 1994;163(3):565–567
  109. McCarthy DS, Pepys J. Pulmonary aspergilloma—clinical immunology. Clin Allergy. 1973;3:57–70
  110. Rafferty P, Biggs BA, Crompton GK, Grant IW. What happens to patients with pulmonary aspergilloma? Analysis of 23 cases. Thorax. 1983;38:579–583
  111. Andrews CP, Weiner MH. Aspergillus antigen detection in bronchoalveolar lavage fluid from patients with invasive aspergillosis and aspergillomas. Am J Med. 1982;73:372–380
  112. Jewkes J, Kay PH, Paneth M, Citron KM. Pulmonary aspergilloma: analysis of prognosis in relation to haemoptysis and survey of treatment. Thorax. 1983;38:572–578
  113. Yamada H, Kohno S, Koga H, Maesaki S, Kaku M. Topical treatment of pulmonary aspergilloma by antifungals. Relationship between duration of the disease and efficacy of therapy. Chest. 1993;103:1421–1425
  114. Munk PL, Vellet AD, Rankin RN, Muller NL, Ahmad D. Intracavitary aspergilloma: transthoracic percutaneous injection of amphotericin gelatin solution. Radiology. 1993;188:821–823
  115. Klein JS, Fang K, Chang MC. Percutaneous transcatheter treatment of an intracavitary aspergilloma. Cardiovasc Intervent Radiol. 1993;16:321–324
  116. Hammerman KJ, Sarosi GA, Tosh FE. Amphotericin B in the treatment of saprophytic forms of pulmonary aspergillosis. Am Rev Respir Dis. 1974;109:57–62
  117. Tsubura E. [Multicenter clinical trial of itraconazole in the treatment of pulmonary aspergilloma. Pulmonary Aspergilloma Study Group]. Kekkaku. 1997;72(10):557–564
  118. Campbell JH, Winter JH, Richardson MD, Shankland GS, Banham SW. Treatment of pulmonary aspergilloma with itraconazole. Thorax. 1991;46:839–841
  119. Dupont B. Itraconazole therapy in aspergillosis: study in 49 patients. J Am Acad Dermatol. 1990;23:607–614
  120. Impens N, De Greve J, De Beule K, Meysman M, De Beuckelaere S, Schandevyl W. Oral treatment with itraconazole of aspergilloma in cavitary lung cancer. Eur Respir J. 1990;3:837–839168-170.
  121. Massard G, Roeslin N, Wihlm JM, Dumont P, Witz JP, Morand G. Pleuropulmonary aspergilloma: clinical spectrum and results of surgical treatment. Ann Thorac Surg. 1992;54:1159–1164
  122. Daly RC, Pairolero PC, Piehler JM, Trastek VF, Payne WS, Bernatz PE. Pulmonary aspergilloma. Results of surgical treatment. J Thorac Cardiovasc Surg. 1986;92:981–988
  123. Uflacker R, Kaemmerer A, Picon PD, et al. Bronchial artery embolization in the management of hemoptysis: technical aspects and long-term results. Radiology. 1985;157:637–644

PII: S1755-0017(08)00077-8

doi:10.1016/j.rmedc.2008.08.008

Respiratory Medicine CME
Volume 1, Issue 3 , Pages 205-215, 2008

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