State of the Art Current Approaches to Diagnosis and Treatment of Invasive Aspergillosis Brahm H. Segal and Thomas J. Walsh Department of Medicine, SUNY at Buffalo, Division of Infectious Diseases, Roswell Park Cancer Institute, Buffalo, New York; and Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Filamentous fungi (moulds) are ubiquitous soil inhabitants whose co- nidia are inhaled into the respiratory tract, where they may cause life- threatening infections. Among these infections is invasive aspergillosis, which is a major cause of morbidity and mortality in the severely immunocompromised. Risk factors for invasive aspergillosis include prolonged and severe neutropenia, hematopoietic stem cell and solid organ transplantation, advanced AIDS, and chronic granulomatous disease. Invasive aspergillosis most commonly involves the sinopulmo- nary tract reflecting inhalation as the principal portal of entry. Chest computed tomography scans and new non-culture–based assays such as antigen detection and polymerase chain reaction may facilitate the early diagnosis of invasive aspergillosis, but have limitations. Reflecting an important unmet need, there has been a significant expansion in the antifungal armamentarium. The second-generation triazole, vori- conazole, was superior to conventional amphotericin B as primary therapy for invasive aspergillosis, and is the new standard of care for this infection. There is significant interest in combination antifungal therapy pairing an echinocandin with either an azole or amphotericin B formulation as therapy for invasive aspergillosis. In addition, there has been an increased understanding of the immunology of Aspergillus infection, paving the way to novel immune augmentation strategies in animal models that merit evaluation in phase I clinic trials. Keywords: Aspergillus; immunocompromised; neutropenia; transplant CONTENTS Patients at Risk for Invasive Aspergillosis Neutropenia Hematopoietic Stem Cell Transplantation Solid Organ Transplantation AIDS Chronic Granulomatous Disease Diagnosis of Invasive Aspergillosis Chest Computed Tomography Scans Laboratory Markers Therapy for Invasive Aspergillosis Immune Augmentation Strategies Augmentation of Neutrophil Number Interferon- Innate Pathogen Recognition Pathways Vaccines Genomics (Received in original form May 9, 2005; accepted in final form December 22, 2005) Correspondence and requests for reprints should be addressed to Brahm H. Segal, M.D., Assistant Professor of Medicine, Department of Medicine, SUNY at Buffalo, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263. E-mail: [email protected] Am J Respir Crit Care Med Vol 173. pp 707–717, 2006 Originally Published in Press as DOI: 10.1164/rccm.200505-727SO on December 30, 2005 Internet address: www.atsjournals.org Aspergillus species are ubiquitous soil inhabitants. Alveolar mac- rophages constitute the first line of host defense against aerosol- ized conidia. Neutrophils are the dominant host defense against the invasive hyphal stage. Aspergillus infection causes a spectrum of illnesses reflecting the immune status of the host (Figure 1). Our review focuses on acute invasive aspergillosis, a major cause of mortality in highly immunocompromised patients. Mortality from invasive aspergillosis increased several-fold in the 1980s and 1990s (1, 2), a reflection of more patients under- going treatment for hematologic malignancies and allogeneic hematopoietic stem cell transplantation (HSCT). Deficits in host defense that render susceptibility to invasive aspergillosis are complex, but can be broadly divided into these categories: (1 ) neutropenia, (2 ) qualitative deficits in phagocyte function, and (3 ) deficits in cell-mediated immunity (Table 1). We will review the epidemiology, diagnosis, and management of invasive asper- gillosis, and strategies for immune augmentation. PATIENTS AT RISK FOR INVASIVE ASPERGILLOSIS Neutropenia The risk of invasive aspergillosis is strongly related to the dura- tion and degree of neutropenia. Most cases of neutropenia- associated aspergillosis occur in patients receiving potent cyto- toxic regimens for hematologic malignancies and myeloablative HSCT (3–5). Invasive aspergillosis is also a major cause of mor- tality in patients with aplastic anemia and prolonged neutropenia (6). Multiple cycles of prolonged neutropenia, such as in refrac- tory leukemia, further predispose patients to invasive filamen- tous fungal infection. Small foci of invasive fungal disease may be clinically and radiographically inapparent during the initial cycle of neutropenia, but manifest clinically during a subsequent cycle. Concomitant therapy with systemic corticosteroids and other immunosuppressive agents increase the risk of invasive aspergillosis. Therefore, knowledge about current and prior cy- cles of chemotherapy is key in risk stratification. Hematopoietic Stem Cell Transplantation Allogeneic HSCT recipients have a higher risk of invasive asper- gillosis than do autologous HSCT recipients because of the greater intensity of immunosuppression. The spectrum of patho- gens to which allogeneic HSCT recipients are most susceptible follows a timeline corresponding to the predominant immune defects at different periods (Table 1). In the early stage, neutro- penia after the conditioning regimen is the principal host defense defect. Most cases of invasive aspergillosis in allogeneic HSCT occur after neutrophil recovery in the setting of potent immuno- suppressive therapy for graft-versus-host disease (GVHD) (5, 7–14). There are three likely reasons: (1 ) shortening of the dura- tion of neutropenia period from infusion of larger numbers of myeloid progenitors and treatment with colony stimulating
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