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Aspergillus-Related Lung Disease

Aspergillus-Related Lung Disease

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provided by Elsevier - Publisher Connector Respiratory Medicine CME (2008) 1, 205e215

CME ARTICLE -related disease

Alexey Amchentsev*, Navatha Kurugundla, Anthony G. Saleh

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

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 infec- tion at local and systemic levels and the virulence of the organism. These entities differ clin- ically, radiologically, immunologically, and in their response to various therapeutic agents. Although the can affect any organ system, the 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. ª 2008 Elsevier Ltd. All rights reserved.

Educational Aims: Introduction

To review the clinical spectrum of Aspergillus-related Aspergillus is a ubiquitous soil-dwelling organism that is lung disease. found in humid areas, damp soil or agricultural environ- To discuss the standardized criteria for the diagnosis of ments. It is also found on grain, cereal, moldy flour, and allergic bronchopulmonary . organic decay or decomposing matter. Since the first To review the factors that predispose to the develop- description of aspergillosis in animals by Mayer in 1815 ment of invasive pulmonary aspergillosis. and the first human case of aspergillosis described in 1842 To review the latest diagnostic methods used in diag- by Bennett,1 more than 350 species that belong to the nosis of Aspergillus-related lung disease. genus Aspergillus have been described. Only a few are To discuss recent advances in diagnostic and thera- known to be pathogenic in humans such as Aspergillus peutic approaches to respiratory diseases caused by fumigatus which is responsible for more than 90% of Aspergillus. 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 * Corresponding author. Tel.: þ1 718 780 5835; fax: þ1 718 780 Aspergillus can cause a variety of clinical syndromes 5836. ranging from mild, transient to serious, dissemi- E-mail address: [email protected] (A. Amchentsev). nated disease, particularly in the immunosuppressed host.

1755-0017/$34 ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmedc.2008.08.008 206 A. Amchentsev et al.

Aspergillus-related pulmonary disorders may be classified and pulmonary fibrosis at later stages. into four clinical categories depending on whether the Computed tomography (CT) findings in allergic broncho- host is atopic, non-atopic or immunosuppressed (see pulmonary aspergillosis consist primarily of mucoid Fig. 1). impaction and bronchiectasis involving predominantly the This article reviews the clinical spectrum of Aspergillus- segmental and subsegmental bronchi of the upper lobes. In related lung disease, highlighting the risk factors, clinical one study, the combination of bronchiectasis with mucous picture, and recent advances in diagnostic and therapeutic plugging, , peripheral airspace consolidation, or approaches. ground-glass attenuation (with or without mosaic perfusion or air trapping) enabled radiologists to make a correct 11 Allergic bronchopulmonary aspergillosis diagnosis of ABPA in 84% of cases. In approximately 30% of (ABPA) patients, the impacted mucus has high attenuation or demonstrates frank calcification at CT. Differential diag- nosis includes other causes of mucoid impaction such as Allergic bronchopulmonary aspergillosis is a hypersensi- endobronchial lesions, bronchial atresia, and tivity reaction to Aspergillus , mostly due to bronchiectasis. A. fumigatus. The incidence of ABPA varies from 6% to 20% 5 There is no individual test to establish the diagnosis of of all patients with asthma. It occurs with equal frequency ABPA.6,12 Typically, total serum IgE is elevated, and in both sexes. Most patients are under age 35 years at the cultures reveal Aspergillus spp. Serum IgE could be used as time of diagnosis. In patients with cystic fibrosis, the a marker for flare-ups and responses to therapy.13 e 6 prevalence of ABPA is 0.5 15%. Immediate test reactivity to A. fumigatus antigens The pathogenesis of ABPA is not completely understood. and elevated levels of serum IgG and IgE antibodies to There is no relation between the intensity of exposure to Aspergillus are usually documented.14 airborne Aspergillus spores and rates of sensitization to the 7 Greenberger and Patterson have standardized the fungus as measured by skin testing. Aspergillus-specific criteria for the diagnosis of ABPA (see Fig. 2), not all of IgE-mediated reactions, specific which need to be present for the diagnosis to be made.13,15 IgG-mediated type III hypersensitivity reactions, and A staging system for ABPA has been developed to cate- abnormal T-lymphocyte cellular immune responses all 8e10 gorize the differing presentations of ABPA. These stages are appear to play important roles in its pathogenesis. ABPA not necessarily progressive phases and do not necessarily is characterized pathologically by mucoid impaction of the occur in order.16 Stage I is the acute initial presentation bronchi, eosinophilic , and bronchocentric with asthma, markedly elevated IgE level, peripheral granulomatosis in addition to the histological features of 6 eosinophilia, upper and middle lobe infiltrates, and IgE and asthma. ABPA is usually suspected on clinical grounds, but IgG antibodies to A. fumigatus. In Stage II (remission stage), requires immunological and radiological confirmation in an the IgE falls but usually remains elevated, eosinophilia is appropriate clinical setting. The disease manifests itself absent, and no infiltrates are noted on the chest radio- with low-grade fever, , wheezing, brown mucus plugs, graph. Serum IgG antibodies to Aspergillus may be and progressive . Pleuritic chest pain and slightly elevated. Stage III is recurrence with the same are frequent. Repeated episodes of bronchial findings as in stage I. Stage IV (the corticosteroid-depen- obstruction, inflammation, and mucoid impaction can lead 6 dent stage) occurs in patients who have asthma in which to bronchiectasis, fibrosis, and respiratory compromise. control of symptoms is dependent on chronic use of high- Chest radiologic findings may show fleeting pulmonary dose corticosteroid therapy and exacerbations are marked infiltrates in the upper lobes and central in location during by worsening asthma, radiographic changes, and an acute exacerbations. The radiological signs representing increase in IgE level may occur. Frequently, the chest CT the thickened and inflamed bronchi may be seen on chest scan will show central bronchiectasis. In stage V (fibrotic radiographs with the development of central stage), bronchiectasis and fibrosis develop, and usually lead

Pulmonary aspergillosis clinical syndromes

Invasive aspergillosis Allergic or Saprophytic Mycotoxicosis hypersensitivity colonization reactions

Generalized or disseminated Localized or limited Allergic asthma Chemical a. Aspergillosis pneumonia Chronic necrotizing Allergic bronchopulmonary (mycetoma or fungus ball) b. Angioinvasive aspergillosis pulmonary aspergillosis aspergillosis c. Lung and multiple cavities Extrinsic allergic alveolitis d. Aspergillosis / tracheobronchitis Bronchocentric granulomatosis e. Infarction f. and

Figure 1 Pulmonary aspergillosis clinical syndromes. Aspergillus-related lung disease 207

Diagnostic criteria for ABPA necrotizing obstruct and destroy the bronchi- oles. The Aspergillus hyphae can be identified within the • Asthma granulomas in up to 50% of patients with bronchocentric 27 • Immediate skin reactivity to Aspergillus granulomatosis. The eosinophilic infiltrates and fibrosis • Serum precipitins to A fumigatus are present in the lung parenchyma; however, there is no • Increased serum IgE and IgG to A fumigatus tissue or vascular invasion by the Aspergillus. Clinically, the • Total serum IgE>1000 ng/ml patients are almost always asthmatic and have a persistent • Current or previous pulmonary infiltrates cough with typical findings of elevated peripheral • Central bronchiectasis eosinophil count, elevated total serum IgE, and circulating IgE antibodies to Aspergillus species. Sputum gram stain • Peripheral eosinophilia (1000 cells/ml) and culture occasionally reveal Aspergillus.28,29 The chest radiograph usually shows solitary or multiple Figure 2 Diagnostic criteria for ABPA. pulmonary nodules that may be mistaken for malignancies. Aspergillus rarely has been implicated in the etiology of to irreversible lung disease. The first four are potentially eosinophilic pneumonitis. reversible, with no long-term sequelae. The final diagnosis The typical presentation of these patients is cough, is usually confirmed by use of clinical, radiographic, and dyspnea, and fever associated with peripheral pulmonary immunologic criteria. infiltrates, and an elevation of Aspergillus IgE levels. The Treatment of ABPA aims to control episodes of acute diagnosis usually is confirmed by biopsy, and patients inflammation and to limit progressive lung injury. Gluco- respond well to corticosteroid therapy.30,31 corticoids are most commonly used, although there is When a patient develops hypersensitivity granulomatous increasing evidence of benefit from combined therapy with inflammation of the distal airways and lung parenchyma, it . The 2008 Infectious Diseases Society of is called extrinsic allergic alveolitis, also known as, hyper- America guidelines on the treatment of aspergillosis sensitivity pneumonitis. This is related to intense or recommend that therapy of ABPA should consist of recurring inhalation of various antigens, including thermo- a combination of and itraconazole.17 philic bacteria, fungi, bird excreta, and chemical agents. Treatment with corticosteroids leads to relief of broncho- The acute form of the disease presents within hours of spasm, resolution of radiographic infiltrates, and reduction exposure to the antigens with dyspnea, cough, fever, and in serum total IgE and peripheral eosinophilia.18,19 Two myalgia. In advanced cases, there may be features of right- weeks of daily therapy of oral prednisone (0.5 mg/kg/day), sided heart failure. The chest radiograph usually shows followed by gradual tapering, has been recommended for interstitial and alveolar nodular infiltrates. In the chronic new ABPA infiltrates.20,21 Most patients, however, require stage, a reticulo-interstitial pattern and honeycombing may prolonged low-dose corticosteroid therapy to control their be seen. Serum levels of IgG antibodies to Aspergillus are symptoms and minimize relapses. elevated when the disease is due to Aspergillus.32 Itraconazole has been effective in improving symptoms, The management of the acute form of hypersensitivity facilitating weaning from corticosteroids, decreasing pneumonitis includes avoiding further exposure to the Aspergillus titers, and improving radiographic abnormali- offending agents and corticosteroid therapy.33,34 ties and pulmonary function.22 Itraconazole is thought to work by reducing the antigenic stimulus for bronchial inflammation.17 The effects can be inferred by IPA the ability of itraconazole to reduce specific Aspergillus IgG.23 One study showed that 46% of patients treated with Invasive pulmonary aspergillosis (IPA) is characterized by itraconazole (200 mg b.i.d. for 16 weeks), had a significant proliferation of fungal mycelia in the pulmonary paren- response, which was defined as a 50% reduction in the chyma. This disease is due to tissue invasion with the fungi. corticosteroid dose, a decrease of at least 25% in the serum It is uncommon and occurs primarily in the setting of IgE concentration, and a 25% improvement in exercise . There have been less than 20 cases tolerance or pulmonary function test results, or the reso- reported in healthy patients. Invasion of the pulmonary lution or absence of pulmonary infiltrates.24 Itraconazole vasculature may result in hemorrhagic infarction. Factors may augment the activity of corticosteroids via inhibition of that predispose to the development of invasive aspergillosis their metabolism, which may lead to abnormal ACTH include , hematopoietic stem-cell and solid stimulation and adrenal insufficiency.25 The usual duration organ transplantation, prolonged and high-dose cortico- of therapy is 3e6 months.6 Total serum IgE serves as therapy, hematological malignancy, cytotoxic a marker of ABPA disease activity, and should be checked therapy, advanced AIDS, and chronic granulomatous 6e8 weeks after the initiation of therapy, then every disease. The risk factors are summarized in (see Fig. 3). 8 weeks for 1 year after that to determine a baseline range Neutropenia is the most important risk factor, and it is for each patient.26 estimated that IPA accounts for 7.5% of all in Patients may develop clinicopathologic syndromes neutropenic patients following induction therapy for acute related to ABPA. The mucoid impaction syndrome may be myelogenous .35 The risk of IPA in these patients is seen without asthma or other features of the disease. The increased with the duration of neutropenia and is esti- patient usually presents with a cough and expectoration of mated to be 1% per day for the first 3 weeks, after which mucus plugs. The mucus plugging may lead to atelectasis. time it increases to 4% per day. The epidemiology of IPA is In patients presenting with bronchocentric granulomatosis, changing and now less than one-third of all patients 208 A. Amchentsev et al.

Major risk factors for invasive the airways and form plugs consisting of mycelia, inflam- pulmonary aspergillosis matory cells, and necrotic debris. These plugs along with the membranes produce resulting in 1. Prolonged neutropenia (<500 cells/mm3 for>10 days) wheezing and dyspnea. Approximately 10% of patients or dysfunction 2. Corticosteroid therapy (especially >3 weeks, high-dose who have invasive aspergillosis develop tracheobronchitis therapy) either alone or with pneumonia. Aspergillus can 3. Transplantation (highest risk is with lung and bone occur in patients with HIV .44 Pleural effusions marrow) or are rare manifestation of invasive 4. Hematologic malignancy (risk is higher with leukemia) aspergillosis.45,46 5. Cytotoxic therapy The diagnosis of IPA remains challenging, and the clini- 6. AIDS (risk increases with lower CD4 count) cian must maintain a high index of suspicion for invasive aspergillosis in patients with risk factors. Definitive diag- Figure 3 Major risk factors for invasive pulmonary nosis of invasive aspergillosis is best made by demonstrating aspergillosis. the characteristic branching septate hyphae in a lung tissue sample along with a culture that is positive for Aspergillus diagnosed with IPA are neutropenic at the time of diag- from the same site. Histopathological diagnosis, by exam- nosis.36 Another significant risk factor for IPA is solid organ ining lung tissue obtained by thoracoscopic or open-lung transplantation, especially after lung and hematopoietic biopsy, remains the‘‘gold standardr‘‘ in the diagnosis of stem-cell transplant. It is estimated that 5% of BMT recip- IPA.47 ients develop IPA with mortality rates ranging between 30% Histopathological examination also allows for the and 80%.36e38 The mortality rate of IPA exceeds 90% in exclusion of other diagnoses, such as malignancy or non- hematopoietic stem-cell transplantation recipients.39,40 IPA fungal infectious diseases. Other fungi such as also has been reported increasingly in patients with HIV and Scedosporium may have comparable appearances, infection. The response to therapy is particularly poor in highlighting the importance of performing a culture for the the HIV-infected population.41 precise identification of the fungus. Rarely, IPA has been reported in the mildly immuno- The significance of isolating Aspergillus spp. in sputum compromised, such as patients with , chronic samples depends on the immune status of the patient. In liver disease, or diabetic ketoacidosis. In a recent review of one study of elderly hospitalized patients with Aspergillus 545 patients with invasive aspergillosis, BMT was the most isolated from the sputum, 92% were consistent with frequent risk factor (32%; autologous BMT, 7%; allogeneic colonization, and only 4.5% had IPA.48 In the immuno- BMT, 25%), followed by hematologic malignancy (29%), solid compromised host sputum culture positivity may be the organ transplantation (9%), and AIDS (8%). In 2% of patients, only indication of IPA. In immunocompetent patients, no underlying risk factors were identified.2 isolation of Aspergillus spp. from the sputum almost The characteristic clinical presentation of invasive always represents colonization with no clinical conse- aspergillosis is a neutropenic individual who is receiving quences and antifungal therapy is generally not indicated. chemotherapy and having persistent fevers despite treat- Some studies have shown that sputum samples that are ment with multiple . The lower respiratory tract positive for Aspergillus in patients with leukemia or in is almost always the primary focus of infection as a result of those who have undergone BMT have a positive predictive the inhalation of Aspergillus spores. Patients present with value of 80e90%.49e51 symptoms that are usually non-specific, and consistent with Alternatively, negative sputum samples do not rule out acute bacterial or (fever, cough, sputum IPA, and it has been shown that negative sputum studies production, and dyspnea). Other symptoms that are have been found in 70% of patients with established significant and raise the possibility of IPA are pleuritic chest IPA.49,52 Blood cultures rarely have positive results.53 pain (due to vascular invasion leading to small pulmonary The chest X-ray may be normal or reveal nodular infarcts) and hemoptysis that is typically mild but can be lesions, patchy infiltrates, or cavitary lesions.54,55 In one massive. IPA is one of the most common causes of hemop- large series of patients, only 10% had a normal chest tysis in neutropenic patients; and has been reported to be X-ray.2 The chest CT scan, especially with high-resolution associated with cavitation that occurs with neutrophil images, is a much more helpful tool in detecting early recovery.42 changes that are not present on chest radiographs. The use With the predilection of Aspergillus to invade blood of high-resolution chest CT scans in patients with sus- vessels, IPA commonly leads to areas of infarction and pected IPA has been associated with better outcomes, hemorrhage in the primary organ (usually the ), and most likely due to earlier diagnosis. Patterson et al showed the organism spreads hematogenously to other organs, that 85% of chest CT scans had findings suggestive of IPA.2 most commonly the brain and rarely the skin, kidneys, and/or high resolution CT were performed in pleura, heart, esophagus, or liver.1 In angioinvasive asper- a study of 33 patients.56 The sensitivity of bronchoalveolar gillosis with vascular dissemination, and lavage (BAL) fluid and washings were 33% and 50% are common. The symptoms are intense pleuritic respectively. CT signs of fungal infection were found in 16 chest pain, sudden dyspnea, tachypnea and hemoptysis. (84%) of 19 episodes. The characteristic CT scan findings Aspergillus can cause a bronchitis/tracheobronchitis are multiple nodules and the (which is an early with severe inflammation of the airways, characterized by radiologic sign that appears as a zone of low attenuation ulcers and membrane formation; most often in AIDS due to hemorrhage surrounding the pulmonary nodule) patients and lung transplant recipients.1,43 Hyphae invade which is primarily seen in neutropenic patients early in the Aspergillus-related lung disease 209 course of disease. Another late radiological sign is the air patients. Most deaths due to IPA occur during the first , which is a crescent-shaped lucency in the 6 weeks after the start of therapy.17,69 region of the original nodule secondary to necrosis.57,58 In Three classes of antifungal agents are available for the spite of the above referenced findings, neither sign is treatment of aspergillosis: polyenes, azoles, and echino- sensitive. The halo sign may be found as a result of candins. Historically, has been the major , bronchoalveolar carcinoma, antifungal drug used in patients with invasive aspergillosis; obliterans organizing pneumonia, , however, is now generally considered the drug or other fungal infection.59 of choice for the treatment of invasive aspergillosis and was Fungal smear and culture of BAL fluid is helpful in the recommended for this indication by the 2008 Infectious diagnosis of IPA, particularly in patients with diffuse lung Diseases Society of America guidelines on the treatment of involvement. The BAL fluid has high specificity attaining aspergillosis.17,70,71 97%,60 but has low sensitivity. The transbronchial biopsies A study which compared voriconazole to amphotericin B do not improve the overall diagnostic yield and are asso- as the primary therapy for IPA showed that voriconazole ciated with increased risks.61 Bronchoscopy may also be had almost 20% higher response rate and a higher survival at useful in detecting Aspergillus antigens in the BAL fluid, week 12.72 These findings suggest that voriconazole is and excluding other infections. superior to standard amphotericin B in patients with inva- Open or thoracoscopic lung biopsies are generally the sive aspergillosis. Voriconazole has a milder side-effect best way to diagnose pulmonary problems in immunocom- profile, and is much better tolerated than amphotericin B, promised patients, but even this procedure is associated but has a significant number of drug-to-drug interactions.73 with approximately 20% false-negative results.62 When BAL If the diagnosis of invasive aspergillosis has not been made, and bronchoscopic biopsy are negative, and a high clinical and the patient is at high risk of , voriconazole suspicion of invasive aspergillosis persists, an open lung is not recommended because it does not have activity biopsy should be performed. against the zygomycetes. The poor candidacy of many patients with suspected Itraconazole is considered a second-line agent for the invasive aspergillosis for surgical or other diagnostic treatment of aspergillosis and is rarely used in immuno- procedures has prompted interest in non-invasive ways for suppressed patients with invasive disease. Voriconazole has diagnosis. Galactomannan is a cell wall glycoprotein that is greater intrinsic activity against Aspergillus species, and released by Aspergillus during growth. The Food and Drug both the intravenous and the oral forms are better toler- Administration recently approved a double-sandwich ELISA ated than itraconazole. The variable bioavailability and for the detection of galactomannan in serum for the diag- potential toxicities of itraconazole limit its use in patients nosis of IPA. Serum galactomannan can be detected several with invasive disease, and the IV formulation has only days before the presence of clinical signs, an abnormal limited data to support its use. In a large nonrandomized chest radiograph, or positive culture. The galactomannan study itraconazole resulted in complete or partial response enzyme immunoassay (EIA) demonstrates proven reliability in 39% and in a failure to respond to treatment in 26% of in patients with hematologic malignancy; however, the patients with IPA. The results were particularly poor in reported sensitivity varies from 44% to 90%.63,64 False- allogeneic BMT recipients and AIDS patients.74 For allergic positive results have been reported in patients receiving syndromes and in less invasive disease, itraconazole b-lactam antibiotics or in those infected with the dimorphic remains a useful alternative. fungi or Blastomyces dermatiti- One of the newest triazoles, , is similar in dis.65 Polymerase chain reaction (PCR) has also been eval- structure to itraconazole. It is well tolerated, but steady- uated and appears promising as a potential diagnostic state levels are not obtained for up to 1 week, potentially modality, but PCR is not yet commercially available for the decreasing its efficacy as primary therapy. Nevertheless, it diagnosis of Aspergillus,66 and is often associated with is effective and safe as salvage therapy in patients with false-positive results, because it does not discriminate invasive aspergillosis refractory to standard antifungal between colonization and infection. therapy.75,76 Long-term use of posaconazole in the treat- Detection of serum (1/3)-b-D-glucan, a fungal cell wall ment of refractory invasive fungal infections appears to be constituent, has recently received FDA approval, and is safe; the most common side effects in one study were a highly sensitive and specific test for invasive deep , gastrointestinal in nature.77 including , , and aspergillosis, that could The most widely used treatment for invasive aspergil- be useful in immunocompromised patients.67 Unfortunately, losis is amphotericin-B. The treatment is recommended to the presence of (1/3)-b-D-glucan is not specific for Asper- continue until the infection appears to be clinically gillus but is indicative of invasive fungal infection with several resolved and the immunosuppression improving. The possible fungal .68 The utility of this assay in non- response rate varies greatly from 20% to 83%.78 Lipid based neutropenic and in allogeneic HSCT recipients at high risk for preparations of amphotericin B have been used in an effort IPA is not yet known. Patients with severe immunosuppres- to minimize side effects. These preparations enable the sion, particularly after BMT have a poor response to therapy infusion of higher doses of amphotericin B with less toxicity compared to less severely immunosuppressed patients (28% and are indicated in patients who are at high risk for vs. 51%, correspondingly).2 Also, the response is better when nephrotoxicity, or have toxic reactions while receiving IPA was limited to the lung as opposed to patients with amphotericin B.79 disseminated infection (40% vs. 18%, respectively).2 The (, , and ani- When a high suspicion of IPA exists empiric therapy dulafungin) are a novel class of antifungal agents with should be started, especially in immunocompromised a unique mechanism of action. They are effective agents 210 A. Amchentsev et al. in the treatment of IPA resistant to standard treatment, or antigens.91 Confirmation of the diagnosis requires a histo- if the patient cannot tolerate first-line agents.70,80 logical demonstration of tissue invasion by the fungus, and Although all three of the currently available echinocandins the growth of Aspergillus species on culture. The yield of have demonstrated activity against Aspergillus,caspo- transbronchial biopsy specimens or percutaneous aspirates fungin is the only one currently approved by the FDA as is relatively poor, and a thoracoscopic or open-lung biopsy is second-line treatment for invasive aspergillosis. There are rarely performed in these patients. Confirmation of the no prospective randomized studies that show improved diagnosis is thus difficult, and delayed diagnosis is common, efficacy with combination therapy (rather than single which may contribute to the morbidity and mortality asso- agents) in the management of primary IPA. Combination ciated with CNPA. The combination of characteristic clinical therapy of an with either a lipid formulation and radiological findings and either serological results posi- of amphotericin B or triazole agent appears promising, but tive for Aspergillus or the isolation of Aspergillus from cannot be recommended for the routine treatment of respiratory samples is highly indicative of CNPA.86 primary IPA. Controlled randomized prospective studies Patients with CNPA respond to systemic antifungal are needed to document the value of this approach. therapy, but this may be a life-long requirement. Ampho- can be used to debride necrotic tissue and to tericin B was initially used, with favorable results.87,92 remove infected tissue in patients with invasive aspergil- Itraconazole has been used as a maintenance drug, and its losis; however, many neutropenic patients also have slight inhibition of the immune response is deemed to be profound thrombocytopenia, which may complicate or useful for recovery from chronic pulmonary aspergillosis.92,93 preclude surgery as a therapeutic option. Surgery should be Recently, voriconazole has emerged as a primary considered in cases of massive hemoptysis, pulmonary therapy for CNPA, with a complete or partial response seen lesions close to the great blood vessels, or immunocom- in 43% of patients, and improvement or stability in 80%.94 promised patients undergoing resection of residual local- Treatment is best evaluated by using multiple variables ized pulmonary lesions.81,82 such as change of weight, energy levels, improvement of There is a possible benefit from adding immunomodu- symptoms, decreasing levels of inflammatory markers and latory agents (colony-stimulating factors) or interferon- total serum IgE level, improvement in infiltrates, and gamma to the treatment of neutropenic patients suspected a reduction in cavity size.91 to have IPA. This may decrease the degree of immunosup- Surgery should be reserved for patients with reasonable pression, in addition to the use of for the respiratory reserve and no other treatment options. It may treatment of IPA. Colony-stimulating factors stimulate the be appropriate for patients with severe hemoptysis if bone marrow to produce more , and have been embolization fails. Mortality varies in reports from 10 to shown to augment the phagocytic activity of neutrophils 39% when using itraconazole.92 against fungi, including Aspergillus spp.83,84 Aspergilloma Chronic necrotizing pulmonary aspergillosis When Aspergillus colonizes a pre-existing , Chronic necrotizing pulmonary aspergillosis (CNPA) is the a fungus ball composed of fungal hyphae, inflammatory description applied to cavitary lung disease, chronic respi- cells, fibrin, mucus, and tissue debris, may form an asper- ratory symptoms, and serum precipitating antibodies to gilloma (mycetoma). It is generally thought that the pres- Aspergillus spp. Several reports describe direct invasion of ence of Aspergillus in pulmonary cavities reflects Aspergillus into the lung parenchyma, with CNPA thus saprophytic colonization and not actual tissue invasion. described as a subacute or non-angioinvasive form.85 Aspergilloma is the most common and best recognized form Several of these cases, however, report progressive of pulmonary involvement due to Aspergillus. damage to the lung parenchyma without clear evidence of Many cavitary lung diseases are complicated by aspergil- tissue invasion. The term chronic cavitary pulmonary lomas, including and (most common), aspergillosis (CCPA) has been applied to the formation and followed by bronchiectasis, bronchial cysts, bullae, anky- expansion of multiple pulmonary cavities.86 It was found losing spondylitis, , and pulmonary infection.95e97 that these patients usually are middle-aged with evidence Sometimes these patients are asymptomatic; however, of generalized immunosuppression in the form of up to 75% of patients present with hemoptysis98 or mellitus, malnutrition, corticosteroid or radiation therapy, productive cough, chest pain, dyspnea, fever, weight loss, collagen vascular diseases or underlying lung diseases.87,88 or clubbing. Life threatening bleeding may occur from These patients usually present with fever, cough, bronchial blood vessels, and may be due to local invasion of sputum production, and weight loss for several months, but blood vessels lining the cavity, endotoxins released from some patients may be asymptomatic.87 Radiologic findings the fungus, or mechanical irritation of the exposed vascu- in CNPA progress slowly over months or years and include lature inside the cavity.99e101 Although aspergillomas are unilateral or bilateral segmental areas of consolidation with usually single, they may also be present bilaterally. or without cavitation or adjacent pleural thickening, and The diagnosis of pulmonary aspergilloma is usually based multiple nodular areas of increased opacity.89,90 on the clinical and radiographic features, combined with A fungal ball may be seen in nearly one half of the cases.87 serological or microbiologic evidence of Aspergillus spp. Other helpful but non-diagnostic tests include serum IgG At , mycetomas are characterized by the antibodies to Aspergillus (positive results in >90% of the presence of solid, round or oval masses with a soft-tissue patients) and immediate skin reactivity to Aspergillus opacity within a lung cavity.102 Typically, the mass is Aspergillus-related lung disease 211 separated from the wall of the cavity by airspace of variable patients who are not surgical candidates; but hemoptysis size and shape, resulting in the ‘‘crescent’’ or Monod’s usually recurs due to the presence of massive collateral sign.103,104 The aspergilloma usually moves when the patient blood vessels.123 The role of newer antifungal azoles such changes position. Differential diagnosis for the air crescent as voriconazole in the treatment of aspergilloma has yet to sign include angioinvasive aspergillosis, echinococcal cyst, be determined. tuberculosis, Rasmussen in a tuberculous cavity, , bronchogenic carcinoma, hematoma, and Conflict of interest statement 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 None of the authors have a conflict of interest to declare in earliest radiographic sign before any visible changes are seen relation to this work. within the cavity. Reversibility of the pleural thickening cor- responding to the resolution of intracavitary fungal material CME Section has been demonstrated at follow-up radiography and it suggests that the thickening of the cavity wall and pleura is This article has been accredited for CME learning by the due to a hypersensitivity reaction.106 European Board of Accreditation in Pneumology (EBAP). While chest radiography does not clearly delineate You can receive 1 CME credit by successfully answering a cavity, CT scanning of the lungs can be used to demon- these questions online. strate a cavity and any intracavitary structures. Magnetic resonance imaging findings are particularly informative and (a) Visit the journal CME site at http://www.resmedcme. can be used in cases where better resolution of the com. 108 pathology is required. The natural history of aspergil- (b) Complete the answers online, and receive your final loma is variable. In the majority of cases, the lesion score upon completion of the test. remains stable, however, in approximately 10% of cases, it (c) Should you successfully complete the test, you may may decrease in size or resolve spontaneously without download your accreditation certificate (subject to an 102 treatment. Sputum cultures for Aspergillus spp. are administrative charge). 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 Educational questions 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 Answer the following questions: There is no consensus on the treatment of aspergilloma. Treatment is considered only when patients become 1. Which of the following statements is true regarding symptomatic, usually with hemoptysis. Many treatment Aspergillus, please select the following statements: strategies such as inhaled, intracavitary, and endobronchial a. is responsible for less than instillations of antifungal agents have been tried and 80% of invasive disease. reported in small numbers of patients, without consistent b. Aspergillus terreus is known to be pathogenic only in success.112e114 In patients with massive hemoptysis from animals. aspergilloma, administration of amphotericin B percuta- c. Aspergillus is a ubiquitous organism found in cereal, neously guided by CT scan can be effective, with resolution grain, decomposing matter of hemoptysis within a few days.115 The role of intrave- d. Only 100 species were identified belonging to genus nously administered amphotericin B is uncertain, and some Aspergillus so far small studies failed to show a benefit.116 e. Aspergillus can cause a variety of clinical syndromes Itraconazole has been used with some reduction in the size of the fungus ball, especially in Europe and Japan, and I. a, b, c, d True has been shown to penetrate into the aspergilloma.117 II. All False Itraconazole is a useful agent for aspergilloma manage- III. c, e True ment, and mainly because of its high tissue penetration an IV. All True oral form has been used, with radiographic and symp- V. c, d True tomatic improvement in one half to two-thirds of patients, and occasional patients having a complete response.118e120 2. Which of the following statement regarding allergic The major limitation of itraconazole is that it works slowly bronchopulmonary aspergillosis are correct: and would not be useful in cases of life-threatening a. It occurs with equal frequency in both sexes. hemoptysis.22 b. Allergic bronchopulmonary aspergillosis is a hyper- Surgical resection of the cavity and removal of the fungus sensitivity reaction to Aspergillus antigens. ball is usually indicated in patients with recurrent hemop- c. In patients with cystic fibrosis, the prevalence of tysis. Surgical treatment is associated with relatively high ABPA is up to 15%. mortality rates up to 23%.121,122 It is important to risk stratify d. There is no relation between the intensity of expo- these patients to determine if they would tolerate surgery. sure to airborne Aspergillus spores and rates of Bronchial artery embolization should be considered as sensitization to the fungus as measured by skin a temporary measure in life threatening hemoptysis or in testing. 212 A. Amchentsev et al.

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