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Revised November 2002
Why study Aspergillus fumigatus?
Aspergillus fumigatus is the commonest mould causing infection worldwide (Latge, 2001).
It is a ubiquitous fungus, found in high concentrations in human homes, in farm
environments and compost facilities (Beffa, 1998). Recently Aspergillus spp. have been
found in hospital water systems (Warris, 2001; Anaissie, 2002). It is unavoidable in life,
but most individuals don’t become ill from inhaling or ingesting conidia. A. fumigatus
has a most remarkable, probably unique, place amongst infectious agents in causing lifethreatening
infection in those with damaged immune systems (invasive aspergillosis),
disease in those with normal immunity, with or without local tissue damage
(aspergilloma, chronic pulmonary aspergillosis, keratitis, tracheobronchitis) and
hypersensitivity diseases (allergic bronchopulmonary aspergillosis, allergic fungal
sinusitis (eosinophilic fungal sinusitis) and extrinsic allergic alveolitis).
History of aspergillosis The first infection described in man, an aspergilloma, was
described in Edinburgh in 1848 (Bennett, 1948) and many cases of invasive disease in
non-immunocompromised patients were reported from the UK, France and Germany
between 1890 (Wheaton, 1890) and 1947 (Cawley, 1947). These cases and more recent
series (Gefter,1981; Karam, 1986; Karim, 1997) emphasise that A.fumigatus is a primary,
albeit rare, pathogen of man. Allergic disease due to Aspergillus was first described by
Popoff in 1887 and classified in London in 1952 (Hinson, 1952).The first invasive (and
fatal) infection in an immunocompromised patient was described in 1953 in the British
Medical Journal in a patient from Gloucester (Rankin, 1953) and several series from the
USA in the middle 1950's emphasised the growing importance of invasive aspergillosis.
(Zimmerman, 1955; Torack, 1957; Finegold, 1959).
Invasive aspergillosis Invasive aspergillosis (IA), caused principally by A. fumigatus, is
now the leading cause of infectious death in leukaemic patients and in patients who
have undergone bone marrow transplantation, affecting between 5 and 25% of all cases
(Denning, 1998; Patterson, 2000). Certain subgroups such as non-ablative peripheral
stem cell transplants (so-called mini-transplants) have a frequency of invasive fungal
infection (IFI) of 23%, mostly IA (Walsh, 2002) and those receiving Infliximab (anti-TNF
monoclonal antibody) for unremitting graft versus host disease have nearly a 50% rate
of IA (Marty, 2002). IA is also a life-threatening infectious complication of heart, heartlung,
lung and liver transplantation (affecting between 4 and 21% of all cases).
The frequency of invasive disease has risen ~14-fold over the 12 years up to 1992, as
judged after death in unselected autopsies, and invasive aspergillosis has overtaken
candidiasis as the most frequent fungal pathogen found after death in tertiary care
hospitals in Europe (Groll, 1997). Thus 4% of all patients dying in modern tertiary care
hospitals had invasive aspergillosis, compared with about 2% with invasive candidiasis.
Another study confirmed this high figure (Voseger, 1999). Recent US data from the CDC
shows that the number of cases of invasive aspergillosis exceeds those of candidiasis
(McNeil, 2001). Patients at risk (frequency of disease) include those with chronic
granulomatous disease (25-40%), lung transplant recipients (17-26%), allogeneic bone
marrow transplant patients (4-30%), neutropenic patients with leukaemia (5-25%), heart
transplant recipients (2-13%), pancreas transplantation (1-4%), renal transplantation in
Europe and the USA (~1%) and in India (~10%), AIDS, multiple myeloma and severe
combined immunodeficiency (~4%) (Denning, 1998). Over 500,000 transplants are done
annually in the world. Acute leukaemia affects about 3/100,000 of the population and on
average each patient receives 3 cycles of chemotherapy, all of which are major risk
periods. Similar figures are found for high grade lymphoma patients who are also at
high risk of invasive aspergillosis. In the industrialised nations alone this would mean
about 250,000 periods of major risk per year. AIDS is a growing problem and failure of
antiretroviral therapy common as a result of poor compliance or early treatment
accelerating the development of resistance in HIV. Worldwide >40 million cases of AIDS
occur, with major new foci in India and China and aspergillosis complicates 4% of these
(Khoo, 1994)
The crude mortality from invasive aspergillosis is around 85% and falls to around 50% if
treatment is given (Denning, 1996; Lin 2001). The new drugs in trial (voriconazole etc)
may reduce the mortality slightly (~10-15%) (Maertens, 2001; Herbrecht, 2002; Denning,
2002) but patients in trials tend to do better than those treated in clinical practice.
Aspergillosis in normal individuals In addition to invasive disease, Aspergillus causes a
number of other diseases in man. These include invasive aspergillosis (Karam, 1986),
aspergilloma ("colonisation" of existing pulmonary cavities) (Raferty, 1983; Chen 1997) ,
chronic (necrotising) pulmonary aspergillosis (Gefter, 1981; Denning, 2001),
tracheobronchitis (Kemper, 1993), saprophytic sinusitis (Stammberger, 1984), usually of
the maxillary sinuses, keratitis (which usually leads to blindness in that eye and is
common in the developing world) (Thomas, 1994), ototis externa (Chander, 1996) and
postoperative infections in normal people (Denning, 1999). Aspergilloma numbers are
set to rise dramatically with the increasing problem with tuberculosis and aspergillomas
are notoriously difficult to treat. Cavities of 2cm or larger after tuberculosis
subsequently develop aspergillomas in 15-20% of patients (in the UK). The 5 year
survival of patients with aspergillomas is about 40%.
Hypersensitivity diseases related to Aspergillus Allergic bronchopulmonary aspergillosis
occurs in patients with cystic fibrosis and asthmatics (an increasing number)
(Greenberger, 1994; Stevens, 2003). The frequency of ABPA in cystic fibrosis is 10-15%
depending on the criteria for diagnosis (Stevens, 2003) . The frequency in patients with
asthma is difficult to ascertain, but may be as high as 5% in adults. There are also
suggestions that allergy to fungi exacerbates asthma, without these patients having
ABPA (Zureik, 2002). Untreated ABPA leads to problematic asthma, often requiring
high doses of corticosteroids with their consequent side-effect. Central bronchiectasis is
one of the structural defects arising from ABPA, and is so characteristic that it is one of
the criteria for diagnosis. Many years of poorly controlled ABPA also causes pulmonary
fibrosis. A recent controlled trial of itraconazole against placebo showed a significant
improvement in those treated with itraconazole, and incidentally was the first ever
study demonstrating the benefit of an antimicrobial agent for an allergic condition
(Stevens, 2000).
Allergic fungal sinusitis is a common problem (Katzenstein, 1983; Schubert, 2002). It has
recently been reunderstood and renamed eosinophilic fungal rhnosinusitis (Ponikau,
1999). The association of nasal polyps, loss of smell and chronic nasal symptoms is
characterisitic. Sinuses are full of eosinophilic mucus, which contain fungal hyphae.
Multiple fungi are probably implicated.
Extrinsic allergic alveolitis (or hypersensitivity pneumonitis) is also related to fungal
exposure, of which Aspergillus spp. is one cause (Greenberger, 2002). Patients develop
cough and breathlessness and diffuse pulmonary infiltrates some hours after exposure,
or chronically if the exposure continues. Pulmonary function tests show poor oxygen
diffusion, and CT scan appearances are characteristic. Removal of the patient from the
fungal environment usually results in complete resolution, although long term
exposures can result in fibrosis and respiratory impairment. Exposures are often
occupational – including in the timber and mushroom industries.
Veterinary diseases Aspergillus is also a pathogen of many vertebrates and some nonvertebrates,
notably the honey bee and scaly weaver (Smith, 1989). Examples of
veterinary disease caused by Aspergillus include pulmonary and airsac infections in
many birds but particularly newly hatched chicks, common crows, mallard ducks, and
parrots and, in outbreaks, penguins in captivity. Both sinusitis and disseminated
infections occur in long-nosed dogs. Bovine abortion, guttural pouch aspergillosis in
horses (which causes catastrophic haemorrhage), and disseminated infections in most
animals including whales and dolphins are occasional problems of undetermined
frequency.
Industrial problems In addition, A.fumigatus is a major economic problem in the timber
industry where wood drying kilns are used. As it survives at high temperature, it tends
to grow on the surface of timber in the kiln and causes a dark green discolouration of the
wood which reduces its value. This costs Scandinavia, for example, millions each year
and is proving difficult to resolve. Exposure of the timber workers to this huge load of
fungal spores leads to a toxic syndrome, akin to extrinsic allergic alveolitis (or farmer's
lung) but more severe, which is incompletely understood.
Species causing disease A. fumigatus is the main pathogen in all these infections with the
exception of sinusitis which is often caused by A. flavus and otitis externa most often
caused by A. niger. A. terreus causes ~2-5% of cases of invasive aspergillosis in humans
but is proportionately more common in dogs. A. nidulans is a rare pathogen but
disproportionately common in patients with chronic granulomatous disease and may
cause mycetoma . About 20 other species of Aspergillus cause disease (see species index,
Aspergillus website). Aspergillus fumigatus has several interesting biological
characteristics including:
• As A. fumigatus is highly thermotolerant and comfortably grows at 50C and can
resist remarkable extremes of external environment (like rocket fuel for
example), it is highly likely that useful enzymes can be isolated from it which
may be of scientific interest. Such enzymes are likely to be involved in complex
synthetic or metabolic pathways which are likely to have intrinsic value. One
such enzyme, a phytase capable of withstanding 100C for 20min (Pasamontes,
1997) is one example. Another example is the metabolic product fumigillin which
appears to inhibit endothelial cell proliferation and is being looked at as a novel
chemotherapeutic agent (Ingber, 1990) and for the treatment of microsporidiosis
(Molina, 2002).
• A.fumigatus is haploid and therefore 'easy' to genetically engineer (Brookman
2001). The single and multiple gene disruptions that have been done point the
way to a straightforward way to assign function to unknown genes in the future
which is technically much more straight forward than is the case, for example
with Candida albicans.
• It is likely that A.fumigatus has some pathogenicity characteristics (Latge, 2002)
although proving this when virulence is probably multifactorial is challenging.
• Resistance to itraconazole was first described in A. fumigatus (Denning, 1997),
and this has substantial implications for new drug development. Like A. terreus
which is always resistant to amphotericin B, resistance to amphotericin B has
been demonstrated in A.fumigatus in vivo (Verweij, 1998).
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