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Aspergillus-Related Lung Disease View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Respiratory Medicine CME (2008) 1, 205e215 CME ARTICLE Aspergillus-related lung 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 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. 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 aspergillosis. 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 asthma 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 bronchiectasis 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, atelectasis, 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 antigens, 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 sputum 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 skin 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 type I hypersensitivity 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 pneumonia, 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, cough, wheezing, brown mucus plugs, graph. Serum IgG antibodies to Aspergillus antigen may be and progressive shortness of breath. Pleuritic chest pain and slightly elevated. Stage III is recurrence with the same hemoptysis 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 Aspergilloma Chemical pneumonitis a. Aspergillosis pneumonia Chronic necrotizing Allergic bronchopulmonary (mycetoma or fungus ball) b. Angioinvasive aspergillosis pulmonary aspergillosis aspergillosis c. Lung abscess and multiple cavities Extrinsic allergic alveolitis d. Aspergillosis bronchitis/ tracheobronchitis Bronchocentric granulomatosis e. Infarction f. Pleural effusion and empyema Figure 1 Pulmonary aspergillosis clinical syndromes. Aspergillus-related lung disease 207 Diagnostic criteria for ABPA necrotizing granulomas 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 blood • 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
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