Definition
• Aspergillosis is caused by species of the mold Aspergillus.
• Syndromes range from colonization; fungus ball due to Aspergillus (aspergilloma); allergic responses to Aspergillus, including allergic bronchopulmonary aspergillosis; to semi-invasive or invasive infections, from chronic necrotizing pneumonia to invasive pulmonary aspergillosis and other invasive syndromes.
Epidemiology
• The highest incidence of infection occurs in patients undergoing hematopoietic stem cell transplantation or solid-organ transplantation (see Table 259-2).
• Infection is more likely in patients with extensive immunosuppression or in those with relapse or recurrence of underlying malignancy.
• Improved survival has been noted with early diagnosis and newer therapies, but mortality rates in severely or persistently immunosuppressed patients are substantial.
Microbiology
• Culture-based diagnosis is useful to establish the specific diagnosis.
• Aspergillus species complexes exhibit distinct antifungal susceptibilities so that culture-based diagnosis is clinically relevant (see Table 259-1).
• Molecular analysis is required to establish species-level identity.
• Increasing rates of antifungal resistance are reported in some settings with a global clone of antifungal-resistant species.
Diagnosis
• Proven infection is established by culture of the organism.
• Biomarkers such as galactomannan, β-d-glucan, and polymerase chain reaction assay are useful for establishing probable diagnosis.
• Serial assessment of biomarkers may be useful for measuring response to therapy.
Therapy
• Voriconazole is recommended for primary therapy in most patients (see Table 259-4).
• Liposomal amphotericin B can be used as primary therapy in patients in whom voriconazole is not tolerated or contraindicated because of drug interactions or other reasons.
• Alternative agents for salvage therapy include amphotericin B lipid complex, the echinocandins (caspofungin, micafungin, or anidulafungin), posaconazole, or itraconazole.
• Combination therapy is not recommended for routine use, but some subgroups of patients (e.g., those with early diagnosis of infection based on detection of galactomannan or those with failure of primary therapy with a single agent) may benefit from such an approach.
Prevention
• Antifungal prophylaxis with posaconazole or possibly voriconazole is recommended in high-risk patients.
• The risk-benefit ratio of prophylaxis in individual patients at risk should be considered.
• Infection control is important to reduce risk in hospitalized patients, but long duration of risk (>180 days) in high-risk hematopoietic stem cell transplant or solid-organ transplant patients makes community-acquired infection likely.
Invasive aspergillosis is a major cause of morbidity and mortality in immunosuppressed patients. This infection is caused by Aspergillus, a mold with hyaline hyphae that is the etiologic agent in invasive aspergillosis and a variety of noninvasive or semi-invasive conditions. These syndromes range from colonization, such as fungus ball due to Aspergillus (also known as aspergilloma); allergic responses to Aspergillus, including allergic bronchopulmonary aspergillosis (ABPA); to semi-invasive or invasive infections, from chronic necrotizing pneumonia to invasive pulmonary aspergillosis and other invasive syndromes.
Aspergillus and the resultant aspergillosis are a major focus of clinical mycology because the number of patients with this disease has risen dramatically and because of the morbidity and mortality of this infection. The increased number of Aspergillus infections has occurred because more patients are at risk for this infection. Patients with established invasive aspergillosis have poor outcomes. Successful therapy depends not only on an early diagnosis but also on reversal of underlying immune defects. Even when therapy is begun promptly, outcomes are often poor, particularly in patients with disseminated or central nervous system disease and in those who remain profoundly immunosuppressed. New diagnostic approaches and new management strategies have been established. In this chapter, clinical mycology, epidemiology, pathogenesis, clinical presentation, diagnosis, treatment, and prevention of aspergillosis are described.
Mycology
The genus Aspergillus was first recognized in 1729 by Micheli, in Florence, who noted the resemblance between the sporulating head of an Aspergillus species and an aspergillum used to sprinkle holy water. In 1856, Virchow published the first complete microscopic descriptions of the organism. Aspergillus flavus was formally named by Link in 1809. Thom and Church first classified the genus in 1926 with 69 Aspergillus species in 11 groups. The term “group” is now more correctly referred to as “section,” but this reporting is not commonplace in clinical mycology laboratories. Because phenotypic methods and internal transcribed spacer sequencing identify Aspergillus isolates within a section and not individual species, it has been recommended that isolates should be reported as members of a “species complex.”
With the recent use of molecular techniques to characterize pathogenic fungi, aspergilli have now increased dramatically to include more than 250 species in eight subgenera (Aspergillus, Fumigati, Circumdati, Candidi, Terrei, Nidulante, Warcupi, and Ornati), which are subdivided into multiple sections and species complexes.
Most species of Aspergillus reproduce asexually, but a teleomorph (or sexual form with a fruiting body) has been identified for a number of species, including pathogenic species such as Aspergillus nidulans (teleomorph, Emericella nidulans), A. amstelodami (Eurotium amstelodami), A. udagawa (Neosartorya udagawae), and the most common pathogen A. fumigatus (Neosartorya fumigata) and many others. Even though the correct taxonomic nomenclature would rename these organisms using the sexual form, generally the generic name Aspergillus has been retained to simplify nomenclature regardless of their teleomorphs (sexual forms), rather than separating the organisms into unfamiliar species based on discovery of a sexual state. As with other pathogenic fungi, the taxonomy of Aspergillus has undergone extensive reclassification with utilization of molecular studies, such as sequencing of ribosomal, β-tubulin, calmodulin, or rodlet A genes, which has allowed more natural subgroupings of ascomycetous fungi. With identity established by means of molecular sequencing, the result of a familiar species may be reported as an unfamiliar telemorph, which has led to assigning one name to one fungus to clarify this potential confusion in clinical mycology.
The genus Aspergillus is an anamorphic member (asexual form) of the family Trichocomaceae. The teleomorphs (sexual forms) of Aspergillus species are classified in eight genera in the order Eurotiales in the phylum Ascomycota. Identification of the genus and of common pathogenic species is usually not difficult, but species-level identification of less common members can be laborious and misidentification of atypical or “cryptic” members of sections—such as poorly sporulating forms—is common.
The most common species causing invasive infection is Aspergillus fumigatus, the most common pathogen in the section Fumigati, which historically has made up a vast majority of invasive isolates: A. flavus; Aspergillus terreus; and, less commonly for invasive infection, Aspergillus niger. Recent studies have shown emergence of less common species, including A. terreus and unusual, less pathogenic species as the etiologic agents of invasive infection, including many “cryptic species” that are identifiable only by molecular studies. With more prolonged and profound immunosuppression—along with molecular identification of cryptic species within a species complex, the list of rare species causing invasive infection continues to increase, including A. alabamensis, A. alliaceus (teleomorph, Petromyces alliaceus), A. avenaceum, A. caesiellus, A. candidus, A. carneus, A. chevalieri (teleomorph, Eurotium chevalieri), A. clavatus, A. calidoustus, A. flavipes, A. fumigatiaffinis, A. glaucus, A. granulosus, A. insuetus, A. keveii, A. lentulus, A. nidulans (Emericella nidulans), A. novofumigatus, A. ochraceus, A. oryzae, A. puniceus, A. pseudodeflectus, A. restrictus, A. sydowii, Emericella quadrilineata (anamorph, A. tetrazonus), A. tamarii, A. tanneri, A. udagawa (Neosartorya udagawae), A. tubingensis, A. versicolor, A. viridinutans, A. vitus (teleomorph, Eurotium amstelodami), A. wentii, Neosartorya pseudofischeri, and many others, although the authenticity of at least some of these has been questioned and perhaps misidentified prior to molecular studies.
Pathogenic Aspergillus species are easily cultured from pathologic samples and grow rapidly (in 24 to 72 hours) on a variety of media. Blood cultures are uncommonly positive and usually reflect contamination rather than invasive disease. A distinguishing characteristic of pathogenic Aspergillus species is their ability to grow at 37° C. A. fumigatus is able to grow at 50° C, a feature that, in addition to morphology, can also be used to identify this species and can help distinguish A. fumigatus from cryptic Aspergillus species in the A. fumigatus complex. Most species initially appear as small, fluffy white colonies on culture plates within 48 hours. Presumptive identification of an Aspergillus species complex is usually accomplished by appearance of the fungus on gross and microscopic inspection of the colony, which provides typical sporulation, although specific species-level identification requires molecular confirmation so that laboratories should report isolates identified phenotypically as a “species complex.”
Microscopic features and colony morphology for the most common clinical isolates, A. fumigatus, A. flavus, A. terreus, and A. niger, are described in Table 259-1 and shown in Figures 259-1 to 259-4. Species-level identification of Aspergillus has become increasingly important because of differences in antifungal drug susceptibility.