By Fernando A. Fernandez, Ph.D., EMLab P&K Mycologist
The genus Aspergillus is an extremely important fungal group and possibly the one with the greatest overall impact in human affairs and civilization. This fungus was first recognized by the botanist P. A. Micheli, who described it in his Nova Plantarum Genera publication in 1729. Throughout human history, members of this fungal genus have gained particular notoriety because of their uncanny ability to produce enzymes, acids, and mycotoxins. An indication of the biochemical importance of this group is the fact that 147 US patents involving Aspergillus metabolites were filed between 1971 and 1991, and many more have been filed since then (Klich 2002).
Aspergillosis is generally defined as a spectrum of diseases of humans and animals caused by members of the genus Aspergillus. In 1863, the German physician/botanist Georg Fresenius is credited with first describing the most notorious disease-causing species in the genus, A. fumigatus, from an infection in a great bustard (a bird), and thereby coined the term aspergillosis to describe the condition (Bennett 2009). Prior to 1863, reports of suspect Aspergillus infections in birds were made by Reaumur in 1749 in describing 'moulding' of eggs, infections of the thoracic air sacs of a duck by Montagu in 1803, and those of a jay by Mayer in 1815 (Bennett 2009). It comes as no surprise that A. fumigatus is predominant in causing animal mycoses, specifically avian aspergillosis, which once accounted for 10% of losses of broiler chicks (Klich 2002), and mycotic abortion in cattle, sometimes affecting up to 10% of the pregnant cows in a herd (Pier & Richard 1992). Other animals involved in agriculture, such as horses and bees, companion animals, particularly dogs and parrots, and zoological or wildlife animals, such as dolphins, raptors and waterfowl, are also at risk (Stevens 2009).
Rudolf Virchow was the first to accurately describe human aspergillosis in 1856, with a less definite report made by Sluyter in 1847. The first known occupational mycoses were cases of aspergillosis reported in 1897 among squab feeders and wig cleaners; all presumed to have been repeatedly exposed to heavy amounts of A. fumigatus spores (Bennett 2009). It should be pointed out that irrespective of occupations, it is common for spores of Aspergillus to enter our bodies continuously through the respiratory system, at rates of hundreds per day without creating any complications in healthy individuals (Hospenthal et al. 1998). However, those individuals with compromised immune systems, especially those recipients of stem-cell and solid organ transplants, those undergoing chemotherapy and those with advanced HIV infection, are particularly at risk in developing the disease when exposed to the fungus. Healthcare-associated aspergillosis is most commonly acquired via inhalation of airborne spores resulting in pulmonary aspergillosis and subsequently the fungus may disseminate via the bloodstream to involve other organs (Weber et al. 2009).
In the clinical setting, aspergillosis has been subdivided into different subtypes, to reflect the spectrum of diseases it encompasses. These general types are: aspergilloma ('fungus ball'), allergic bronchopulmonary aspergillosis (ABPA) and invasive (systemic) aspergillosis (IA). Aspergilloma is the saprobic colonization of a preexisting cavity in the lungs by an Aspergillus species. The fungus characteristically forms a compact mycelial ball which does not invade adjacent tissues. In ABPA, airway infections with Aspergillus exacerbate asthma symptoms in patients with chronic asthma and cystic fibrosis. Aspergillus fumigatus is the most commonly implicated species, although other species can also be involved (Goldman & Huffnagle 2009). In contrast, IA is characterized by mycelium of the fungus growing between epithelial cells, becoming primarily localized in the lungs, and disseminating through the circulatory system with severe immunosuppression as an essential precondition (Hoog et al. 2002).
Invasive aspergillosis has become particularly serious and has increased during the past two decades, primarily due to the broad use of chemotherapies and immunosuppressive therapies in many different patient groups (Mascheyer et al. 2009). Risk groups include recipients of hematopoietic stem cell transplants (HSCT), solid-organ transplants, patients undergoing chemotherapy and patients with advanced HIV infections (Weber et al. 2009). In 2002, a cooperative effort named TRANSNET was created among academic institutions and the Centers for Disease Control (CDC). This multi-institutional collaboration serves as a surveillance network of 25 transplant centers in hospitals that perform stem cell and/or solid organ transplants in the U.S., to monitor the incidence of invasive fungal infections in transplant recipients (Morgan et al. 2005). The network has provided important information on the epidemiology of IA infections in the United States (Weber et al. 2009), including details of which species of Aspergillus have been involved in infections. Aspergillus fumigatus is still prevalent (56-60%), followed by A. flavus (9-19%), A. terreus (12-16%), A. niger (8-18%), and A. versicolor (1%) (Baddley et al. 2003, Morgan et al. 2005). These data contrast with earlier epidemiologic data from a decade earlier when the vast majority of cases (90%) were secondary to A. fumigatus (Marr et al. 2002). Other species such as A. glaucus, A. nidulans, A. oryzae and A. ustus have also been involved in healthcare-associated aspergillosis outbreaks (Weber et al. 2009).
Early diagnosis is critical for a favorable outcome in patients with systemic fungal infections, and particularly with aspergillosis. However, diagnosis remains challenging due to the low sensitivity of microbiological culture techniques and the low specificity of radiological procedures (Maschmeyer et al. 2009). More sensitive diagnostic tests have been developed based on detecting Aspergillus-specific molecules with immunosorbent techniques (ELISA) and DNA techniques by using PCR; the latter are not yet commercially available and are not standardized (Maschmeyer et al. 2009).
Powerful antifungal agents are currently used to treat patients with aspergillosis. Those include amphotericin B, triazoles (itraconazole, voriconazole and posaconazole) and echinocandins (caspofungin, micafungin, anidulafungin) (Stevens 2009). Problems with these drugs include the development of resistance, toxicity, and harmful interactions with other drugs. A good example of drug resistance is shown by A. terreus which consistently show decreased susceptibility to amphotericin B in vitro and in vivo (Baddley et al. 2003). On the preventative front, there is research work in progress to develop a vaccine that could provide protection against A. fumigatus, with promising results in laboratory mice (Ito et al. 2009).
In the indoor environment, Aspergillus can be found in household dust, building materials, ornamental plants, flower arrangements, tobacco, food and water (Warris & Verwej 2005). Dispersal of fungal structures (spores, hyphal fragments) is impacted by activities such as construction, demolition, excavation, disturbance of dust accumulations during routine cleaning, water intrusion and moisture accumulation. In addition, aspergillosis outbreaks in healthcare facilities have been associated with contaminated air conditioners, air filters, particle board frames of air filters, air duct systems, ceiling tiles and fireproofing materials (Haiduven 2009). However, concentrations of Aspergillus spores have not been found to be correlated to any seasonal pattern or the occurrence of invasive aspergillosis (Hospenthal et al. 1998). Also, the relationship between airborne spore counts and infection risk has been difficult to assess because it has been impossible to relate a specific number of airborne spores to a quantifiable infection risk among patients, including highly immunocompromised patients. For this reason, the CDC has not provided recommendations regarding routine microbiologic air sampling before, during, or after facility construction or renovation, or before or during occupancy of areas housing immunocompromised patients (Weber 2009).
The CDC provides excellent on-line resources, including several publications with guidelines to managing infectious agents (http://www.cdc.gov/hicpac/pubs.html). Also, the mycotic disease branch of the CDC has a web page with relevant and updated information on fungal diseases (http://www.cdc.gov/nczved/divisions/dfbmd/mdb/).
It is important to keep in mind that members of the genus Aspergillus are all free-living, saprobic species that can potentially become opportunistic pathogens (Bennett 2009). There is no evidence that these fungi derive obvious benefits from parasitizing humans, other animals, or that they have evolved to take advantage of living hosts. It is then reasonable to conclude that their ability to cause disease stems from their overall ability to survive under a wide array of living conditions. Then it is also reasonable to conclude that management of Aspergillus and the disease-casuing members of this genus will remain an important issue in the management of environmental and clinical health in the future.
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This article was originally published on July 2010.