Eur Respir Rev 2011; 20: 121, 156–174 DOI: 10.1183/09059180.00001011 CopyrightßERS 2011 REVIEW Pulmonary aspergillosis: a clinical review M. Kousha, R. Tadi and A.O. Soubani ABSTRACT: Aspergillus is a mould which may lead to a variety of infectious, allergic diseases AFFILIATION depending on the host’s immune status or pulmonary structure. Invasive pulmonary aspergillosis Division of Pulmonary Critical Care and Sleep Medicine, Wayne State occurs primarily in patients with severe immunodeficiency. The significance of this infection has University School of Medicine, dramatically increased with growing numbers of patients with impaired immune state associated Detroit, MI, USA. with the management of malignancy, organ transplantation, autoimmune and inflammatory conditions; critically ill patients and those with chronic obstructive pulmonary disease appear to CORRESPONDENCE A.O. Soubani be at an increased risk. The introduction of new noninvasive tests, combined with more effective Division of Pulmonary Critical Care and better-tolerated antifungal agents, has resulted in lower mortality rates associated with this and Sleep Medicine infection. Chronic necrotising aspergillosis is a locally invasive disease described in patients with Wayne State University chronic lung disease or mild immunodeficiency. Aspergilloma is usually found in patients with School of Medicine Harper University Hospital previously formed cavities in the lung, whereas allergic bronchopulmonary aspergillosis, a 3990 John R - 3 Hudson hypersensitivity reaction to Aspergillus antigens, is generally seen in patients with atopy, asthma Detroit or cystic fibrosis. This review provides an update on the evolving epidemiology and risk factors of MI 48201 the major manifestations of Aspergillus lung disease and the clinical manifestations that should USA E-mail: [email protected] prompt the clinician to consider these conditions. Current approaches for the diagnosis and management of these syndromes are discussed. Received: Jan 23 2011 KEYWORDS: Aspergillosis, diagnosis, management, pulmonary, risk factors Accepted after revision: March 10 2011 PROVENANCE spergillus spp. are widespread in the clinical presentations, radiological features, diag- Submitted article, peer reviewed. environment and are commonly isolated nostic criteria, management options and outcome. A from both the outdoor environment (i.e. soil, plant debris) and indoor environment, INVASIVE PULMONARY ASPERGILLOSIS including hospitals. Pulmonary disease is caused IPA was first described in 1953 [3]. Due to mainly by Aspergillus fumigatus and has a widespread use of chemotherapy and immuno- spectrum of clinical syndromes (fig. 1) [1]. suppressive agents, its incidence has increased over the past two decades [4, 5]. Of all autopsies Invasive pulmonary aspergillosis (IPA) is a performed between 1978 and 1992, the rate of severe disease, and can be found not only in invasive mycoses increased from 0.4% to 3.1%, as severely immunocompromised patients, but also documented by GROLL et al. [6]. IPA increased in critically ill patients and those with chronic from 17% to 60% of all mycoses found on autopsy obstructive pulmonary disease (COPD). Chronic over the course of the study. The mortality rate of necrotising aspergillosis (CNA) is locally inva- IPA exceeds 50% in neutropenic patients and sive and is seen mainly in patients with mild reaches 90% in haematopoietic stem-cell trans- immunodeficiency or with a chronic lung dis- plantation (HSCT) recipients [7, 8]. ease. Aspergilloma and allergic bronchopulmon- ary aspergillosis (ABPA) are noninvasive forms Risk factors of Aspergillus lung disease. Aspergilloma is a fungus ball that develops in a pre-existing cavity Alveolar macrophages are the first line of defence within the lung parenchyma, while ABPA is a against inhaled Aspergillus conidia. In the lungs, hypersensitivity manifestation in the lungs that pathogen recognition receptors, such as Toll-like almost always affects patients with asthma or receptors, dectin-1 and mannose-binding lectin, cystic fibrosis [2]. identify specific fungal wall components and produce cytokines that stimulate neutrophil rec- This review systematically describes the main ruitment, the main defence mechanism against European Respiratory Review clinical syndromes associated with pulmonary Aspergillus hyphae [9]. The major risk factor Print ISSN 0905-9180 aspergillosis, covering their incidence, risk factors, for IPA is immunodeficiency (table 1), which Online ISSN 1600-0617 156 VOLUME 20 NUMBER 121 EUROPEAN RESPIRATORY REVIEW M. KOUSHA ET AL. REVIEW: PULMONARY ASPERGILLOSIS Inhalation of Aspergillus spores Chronic lung disease or Asthma Normal Cavitary Immunocompromised mild immunocompromised Cystic fibrosis host lung disease host host Atopy Chronic Invasive Allergic No sequel Aspergilloma necrotising pulmonary bronchopulmonary aspergillosis aspergillosis aspergillosis FIGURE 1. The spectrum of pulmonary aspergillosis. includes neutropenia, HSCT and solid-organ transplantation, the hazard ratio for IPA in the setting of CMV disease increases prolonged therapy with high-dose corticosteroids, haemato- 13.3-fold (95% CI 4.7–37.7) [8]. logical malignancy, cytotoxic therapy, advanced AIDS and Neutrophil dysfunction is another risk factor for IPA and is chronic granulomatous disease (CGD) [1, 10, 15]. seen primarily in CGD. IPA is an important cause of mortality The most important risk factor is neutropenia, especially when in these patients [22]. there is an absolute neutrophil count of ,500 cells?mm-3. The IPA is relatively uncommon in patients with HIV infection, risk of IPA correlates strongly with the duration and degree of especially with the routine use of highly active anti-retroviral neutropenia. The risk in neutropenic patients is estimated to therapy. The incidence of aspergillosis in a large cohort of increase by 1% per day for the first 3 weeks and then by 4% per patients with HIV infection was 3.5 cases per 1,000 person-yrs day thereafter [10]. HSCT and solid-organ transplantation [18]. A low CD4 count (,100 cells?mm-3) is present in almost (especially lung transplantation) are also significant risk factors all cases of AIDS-associated aspergillosis, and half of HIV- [11, 23] Several other factors predispose patients with trans- infected patients with IPA have coexistent neutropenia or are plantation to acquire IPA: multiple immune defects includ- on corticosteroid therapy. The rest of the cases appear to have ing prolonged neutropenia in the pre-engraftment phase of no particular risk factors other than advanced AIDS [19–21]. HSCT; the use of multiple anti-rejection or anti-graft versus There is increased incidence of tracheobronchial involvement host disease (GVHD) therapy (such as corticosteroids and in these patients in addition to the usual clinical picture of IPA cyclosporine); parenteral nutrition; use of multiple antibiotics; [21, 31]. Since isolation of Aspergillus from respiratory secre- and prolonged hospitalisation. tions has poor predictive value for invasive IPA in AIDS There has been a steady increase in the documented cases of patients, a histopathological diagnosis is usually required to IPA following HSCT, where the risk is much higher following establish the diagnosis [32]. Response to therapy in this patient allogeneic rather than autologous HSCT (incidences of 2.3–15% group tends to be particularly poor [19–21, 32, 33]. The and 0.5–4%, respectively) [8, 12–14, 24]. In allogeneic HSCT, the prognosis of HIV-infected patients with IPA is generally poor, highest risk is in patients with severe GVHD (grade III–IV). The with median survival of 3 months following diagnosis [18]. timeline of IPA in these patients follows a bimodal distribution, There are increasing numbers of reports documenting IPA in with a peak in the first month following HSCT, which is immunocompetent patients who do not have the classic risk associated with neutropenia. The second peak is during the factors. Two at-risk groups stand out: patients with severe treatment of GVHD (median 78–112 days post-transplantation) COPD and critically ill patients. IPA is an emerging serious [8, 13, 25]. Currently, the first peak is less significant because of infection in patients with COPD. The majority of these patients the routine use of stem cells instead of bone marrow for have advanced COPD and/or are on corticosteroid therapy. transplantation, nonmyeloablative regimens, the use of colony- Patients with COPD have increased susceptibility to IPA for stimulating factors during neutropenia and the widespread use several reasons, including structural changes in lung architec- of antifungal agents [13, 26]. The second peak has become more ture, prolonged use of corticosteroid therapy [16], frequent significant, especially with the higher incidence of GVHD hospitalisation, broad-spectrum antibiotic treatment, invasive associated with unrelated allogeneic transplantation and treat- procedures, mucosal lesions and impaired mucociliary clear- ment with intensive immunosuppressive therapy, including ance, and comorbid illnesses such as diabetes mellitus, corticosteroids, cyclosporine A, anti-TNF agents, and other alcoholism and malnutrition. It is also possible that abnorm- T-cell depleting strategies [13, 14, 17, 27–29]. alities or deficiencies in surfactant proteins, alveolar macro- phages and Toll-like receptors play a role in the pathogenesis In a study by MARR et al. [14], the probability of IPA reached of IPA in some patients with COPD