Universitario

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article
Medical Progress

Aspergillosis
Brahm H. Segal, M.D. ilamentous fungi (molds) are ancient lineages that have existed for approximately 1 billion years1 and thrive in soil and decomposing vegetation independent of an animal host. Thus, the evolution from primitive immune systems that rely principally onantimicrobial peptides, such as those in insects,2 to the complex immune system in mammals occurred with continued exposure to fungi. The immune system, therefore, must not only recognize inhaled molds and control their growth but also restrain injurious inflammation and allergy. We regularly inhale the spores of aspergillus species, yet fungal disease is uncommon. Aspergillus-related diseases are associatedwith a spectrum of disorders of immunity. Invasive aspergillosis, the focus of this review, is typically a disease of highly immunocompromised persons and is a leading cause of infection-related death in patients with acute leukemia and recipients of allogeneic hematopoietic stem-cell transplants. At the other end of the immunologic spectrum, allergic forms of aspergillosis, such as allergicbronchopulmonary aspergillosis, result from a poorly controlled inflammatory response to hyphae colonizing the sinopulmonary tract. Important advances have been made in fungal diagnostics and in the antifungal armamentarium. In addition, new insights have been gained regarding host defense against aspergillus species and the immunopathogenesis of aspergillus-related diseases that may pave the way tonew prevention and therapeutic strategies.

From the Departments of Medicine and Immunology, Roswell Park Cancer Institute, Buffalo, NY. Address reprint requests to Dr. Segal at the Departments of Medicine and Immunology, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, NY 14263, or at brahm.segal@ roswellpark.org. N Engl J Med 2009;360:1870-84.
Copyright © 2009 MassachusettsMedical Society.

F

Hos t Defense ag a ins t A spergil lus
Innate Immunity

Respiratory epithelial cells act as an anatomic barrier to invasion by inhaled aspergillus species, promote mucociliary clearance, and ingest inhaled conidia (spores). The ability of aspergillus species to survive within epithelial cells may enable evasion of host defense by phagocytes.3 Alveolar macrophages constitutethe first line of phagocytic host defense against inhaled conidia.4 Peripheral-blood monocytes and neutrophils are subsequently recruited to sites of infection. After fungal germination (transformation from conidia to hyphae), neutrophils are the dominant host defense against hyphae, the tissue-invasive form of molds.4 Natural killer cells are recruited to the lungs by chemokines early inexperimental aspergillosis and play an important host-defense function.5 The NADPH oxidase in phagocytes is essential in host defense against aspergillosis, as demonstrated in patients with chronic granulomatous disease, an inherited disorder of NADPH oxidase. Chronic granulomatous disease is associated with recurrent bacterial and fungal diseases, and invasive aspergillosis is a major cause of death inpatients with this disease.6 The activation of NADPH oxidase results in the conversion of oxygen to superoxide anion and the generation of downstream reactive oxidant metabolites with antimicrobial activity. In neutrophils, the activation of NADPH oxidase is coupled with activation of antimicrobial proteases sequestered
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The New EnglandJournal of Medicine Downloaded from nejm.org on November 2, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved.

medical progress

in primary granules.7 The neutrophil NADPH oxidase is activated by constituents of the fungal-cell wall and is required to induce hyphal damage. In contrast, neutrophil-mediated...