<em>Aspergillus fumigatus</em> and Aspergillosis

Laboratoire des Aspergillus, Institut Pasteur, 75015 Paris, France

^{Mailing address: Laboratoire des}Aspergillus, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France. Phone: 01 40 61 35 18. Fax: 01 40 61 34 19. E-mail: rf.ruetsap@egtalpj.

Abstract

Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia are normally eliminated in the immunocompetent host by innate immune mechanisms, and aspergilloma and allergic bronchopulmonary aspergillosis, uncommon clinical syndromes, are the only infections observed in such hosts. Thus, A. fumigatus was considered for years to be a weak pathogen. With increases in the number of immunosuppressed patients, however, there has been a dramatic increase in severe and usually fatal invasive aspergillosis, now the most common mold infection worldwide. In this review, the focus is on the biology of A. fumigatus and the diseases it causes. Included are discussions of (i) genomic and molecular characterization of the organism, (ii) clinical and laboratory methods available for the diagnosis of aspergillosis in immunocompetent and immunocompromised hosts, (iii) identification of host and fungal factors that play a role in the establishment of the fungus in vivo, and (iv) problems associated with antifungal therapy.

Abstract

Aspergillus fumigatus is a saprophytic fungus that plays an essential role in recycling environmental carbon and nitrogen (235, 506, 676). Its natural ecological niche is the soil, wherein it survives and grows on organic debris. Although this species is not the most prevalent fungus in the world, it is one of the most ubiquitous of those with airborne conidia (443, 444, 466). It sporulates abundantly, with every conidial head producing thousands of conidia. The conidia released into the atmosphere have a diameter small enough (2 to 3 μm) to reach the lung alveoli (518, 577). A. fumigatus does not have an elaborate mechanism for releasing its conidia into the air; dissemination simply relies on disturbances of the environment and strong air currents. Once the conidia are in the air, their small size makes them buoyant, tending to keep them airborne both indoors and outdoors. Environmental surveys indicate that all humans will inhale at least several hundred A. fumigatus conidia per day (99, 222, 271). For most patients, therefore, disease occurs predominantly in the lungs, although dissemination to virtually any organ occurs in the most severely predisposed.

Inhalation of conidia by immunocompetent individuals rarely has any adverse effect, since the conidia are eliminated relatively efficiently by innate immune mechanisms. Thus, until recent years, A. fumigatus was viewed as a weak pathogen responsible for allergic forms of the disease, such as farmer’s lung, a clinical condition observed among individuals exposed repeatedly to conidia, or aspergilloma, an overgrowth of the fungus on the surface of preexisting cavities in the lungs of patients treated successfully for tuberculosis (169, 341, 500). Because of the increase in the number of immunosuppressed patients, however, and the degree of severity of modern immunosuppressive therapies, the situation has changed dramatically in recent years (114, 556, 572). Over the past 10 years, A. fumigatus has become the most prevalent airborne fungal pathogen, causing severe and usually fatal invasive infections in immunocompromised hosts in developed countries (13, 43, 61, 142, 170, 231). A fourfold increase in invasive aspergillosis (IA) has been observed in the last 12 years. In 1992, IA was responsible for approximately 30% of fungal infections in patients dying of cancer, and it is estimated that IA occurs in 10 to 25% of all leukemia patients, in whom the mortality rate is 80 to 90%, even when treated (59, 140, 141, 231, 682). IA is now a major cause of death at leukemia treatment centers and bone marrow transplantation (BMT) and solid-organ transplantation units (119, 159, 489, 575).

Although A. fumigatus is the most common etiologic agent, being responsible for approximately 90% of human infections (61, 159, 169, 334, 350, 587, 676), it is not the only pathogen in this genus. A. flavus, A. terreus, A. niger, and A. nidulans can also cause human infections. Since A. fumigatus is the most common, however, this review is devoted exclusively to it. Fundamental and clinical aspects of the pathobiology of A. fumigatus infections are presented, with special emphasis on IA. The topics discussed include (i) taxonomic characterization of the species, (ii) clinical and laboratory diagnosis of the disease, (iii) host immune response to the fungus and putative fungal virulence factors, and (iv) antifungal drugs used in treatment.

ACKNOWLEDGMENTS

I thank D. Denning and M. Monod for carefully reading the manuscript and adding appropriate comments and corrections, R. Calderone and J. Domer for editing this review, J. P. Debeaupuis for expert computer assistance in preparing all illustrations, M. Cormier for typing the manuscript, and the members of the Aspergillus Laboratory for providing unpublished data and useful comments.

ACKNOWLEDGMENTS

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