Differences in pathogenicity and clinical syndromes due to Aspergillus fumigatus and Aspergillus flavus.
ABSTRACT Most of the information available about Aspergillus infections has originated from the study of A. fumigatus, the most frequent species in the genus. This review aims to compare the pathogenicity and clinical aspects of Aspergillosis caused by A. fumigatus an A. flavus. Experimental data suggests that A. flavus is more virulent than A. fumigatus. However, these were mostly models of disseminated Aspergillus infection which do not properly mimic the physiopathology of invasive aspergillosis, a condition that is usually acquired by inhalation. In addition, no conclusive virulence factor has been identified for Aspergillus species. A. flavus is a common cause of fungal sinusitis and cutaneous infections. Chronic conditions such as chronic cavitary pulmonary aspergillosis and sinuses fungal balls have rarely been associated with A. flavus. The bigger size of A. flavus spores, in comparison to those of A. fumigatus spores, may favour their deposit in the upper respiratory tract. Differences between these species justify the need for a better understanding of A. flavus infections.
- SourceAvailable from: ncbi.nlm.nih.gov[show abstract] [hide abstract]
ABSTRACT: The optimal treatment for invasive aspergillosis remains elusive, despite the increased efficacy of newer agents. The immunosuppressants cyclosporine (CY), tacrolimus (FK506), and sirolimus (formerly called rapamycin) exhibit in vitro and in vivo activity against Candida albicans, Cryptococcus neoformans, and Saccharomyces cerevisiae, including fungicidal synergy with azole antifungals. We report here that both FK506 and CY exhibit a clear in vitro positive interaction with caspofungin against Aspergillus fumigatus by disk diffusion, microdilution checkerboard, and gross and microscopic morphological analyses. Microscopic morphological analyses indicate that the calcineurin inhibitors delay filamentation, and in combination with caspofungin there is a positive interaction. Our findings suggest a potential role for combination therapy with calcineurin pathway inhibitors and existing antifungal agents to augment activity against A. fumigatus.Antimicrobial Agents and Chemotherapy 06/2004; 48(5):1664-9. · 4.57 Impact Factor
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ABSTRACT: A 5-year-old boy with acute lymphoblastic leukemia and probable pulmonary aspergillosis developed a hard, protuberant, white-yellow and aggressive elongated lesion on the left side of his tongue during a febrile agranulocytopenic episode. Despite the use of broad-spectrum antibiotics and other supportive therapies, the lesion increased to about 2x4 cm in size within two days and became grey-black with an erythemateous, irregular line. Partial excision of the tongue was performed and isolates recovered from the tongue biopsy specimen were identified as Aspergillus flavus. An increase in the systemic dose (7 mg/kg/day) and local intraoral delivery of liposomal amphotericin B was successful in treating the patient and resulted in improved clinical and laboratory findings. Herein, we document the observation of tongue aspergillosis in a leukemic child with probable pulmonary aspergillosis receiving liposomal amphotericin B therapy and the successful treatment of tongue aspergillosis with an increased dose (7mg/kg) of liposomal amphotericin B. To the best of our knowledge, this is the youngest patient with documented intraoral aspergillosis and only the second case of tongue aspergillosis caused by Aspergillus flavus.Medical Mycology 01/2007; 44(8):767-70. · 1.98 Impact Factor
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ABSTRACT: Physico-chemical properties of Aspergillus conidia rely on their outer cell-wall rodlet layer. In A. fumigatus and A. nidulans, the rodlet structure is due to an hydrophobin encoded by homologous rodA genes. To evaluate the role of the rodlet structure on the physico-chemical properties of conidia, we compared hydrophobicity, Lewis acid-base (i.e. electron donor/acceptor) characteristics and electrostatic charge of hydrophobin-less (rodletless) mutant and wild-type conidia of A. fumigatus and A. nidulans. The results obtained by aqueous-solvent partitioning assays, microsphere adhesion assays and microelectrophoresis showed that the disruption of the rodA gene modifies surface properties of A. fumigatus and A. nidulans conidia, and confirmed that the rodlet layer plays a key role in their physico-chemical behaviour. The absence of this layer on A. fumigatus spores led to the appearance of weakly basic and acidic characteristics, and had a slight effect on the hydrophobicity of conidia. Whereas in A. nidulans, it induced a basic character, a marked decrease in hydrophobicity and in the polarization capacity (electronegativity) of conidia. These physico-chemical differences between A. fumigatus and A. nidulans rodletless conidia may be attributed to differences in the composition of the conidial outer cell-wall of the two species.Letters in Applied Microbiology 01/2000; 29(6):364-9. · 1.63 Impact Factor
Differences in pathogenicity and clinical syndromes due to
Aspergillus fumigatus and Aspergillus flavus
ALESSANDRO C. PASQUALOTTO
Infection Control Department at Santa Casa Complexo Hospitalar, Porto Alegre, and Post-Graduation Program in
Pulmonary Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
Most of the information available about Aspergillus infections has originated from
the study of A. fumigatus, the most frequent species in the genus. This review aims
to compare the pathogenicity and clinical aspects of Aspergillosis caused by
A. fumigatus an A. flavus. Experimental data suggests that A. flavus is more
virulent than A. fumigatus. However, these were mostly models of disseminated
Aspergillus infection which do not properly mimic the physiopathology of invasive
aspergillosis, a condition that is usually acquired by inhalation. In addition, no
conclusive virulence factor has been identified for Aspergillus species. A. flavus is a
common cause of fungal sinusitis and cutaneous infections. Chronic conditions
such as chronic cavitary pulmonary aspergillosis and sinuses fungal balls have
rarely been associated with A. flavus. The bigger size of A. flavus spores, in
comparison to those of A. fumigatus spores, may favour their deposit in the upper
respiratory tract. Differences between these species justify the need for a better
understanding of A. flavus infections.
Pathogenicity, aspergillosis, Aspergillus flavus, Aspergillus fumigatus,
Infections caused by Aspergillus species have grown in
importance in recent years. This probably results from
a higher number of patients being at risk, including
transplant recipients, neutropenic individuals, allergic
patients and those treated with corticosteroids or other
immunosuppressive regimens. Despite a better under-
standing of the epidemiology of Aspergillus infections,
important diagnostic limitations persist. Accordingly,
the mortality for invasive aspergillosis remains very
high. As most of the Aspergillus infections are caused
by A. fumigatus, the majority of studies have focused on
this species, and our understanding of other Aspergillus
species is far from satisfactory.
Aspergillus flavus is the second leading cause of
invasive and non-invasive aspergillosis . In addition,
it is the main Aspergillus species infecting insects, and it
is also able to cause diseases in economically important
crops, such as maize and peanuts, and to produce
potent mycotoxins. Curiously, some Aspergillus syn-
dromes are rarely associated with A. flavus. The aim of
this review is to summarize the available data compar-
ing the pathogenicity of these two medically important
thermotolerant fungi, A. fumigatus and A. flavus. In
addition, clinical syndromes particularly associated
with A. flavus are presented.
Geographic variations in Aspergillus species
Although not completely understood, climate and
geographic conditions are very important determinants
of the prevalence and distribution of Aspergillus species
in the air we breathe. The marked predominance of
A. fumigatus on clinical samples may simply reflect its
environmental predominance over other Aspergillus
species. However, important geographic variations in
Correspondence: Alessandro C. Pasqualotto, Servic ¸o de Controle de
Infecc ¸a ˜o Hospitalar, Av Independe ˆncia 75, Hospital Dom Vicente
Scherer, 7oandar, Santa Casa de Porto Alegre, Brazil. Tel: ?55 51
99951614; fax: ?55 51 32148629. E-mail: pasqualotto@santacasa.
Received 31 January 2008; Accepted 4 June 2008
– 2008 ISHAMDOI: 10.1080/13693780802247702
2008, S1?S10, iFirst article
the distribution of Aspergillus species occur all over the
globe. For instance, A. flavus is particularly prevalent in
the air of some tropical countries [2?5]. In countries like
Saudi Arabia and Sudan, with semi-arid and arid dry
weather conditions, A. flavus is frequently described as
a leading cause of invasive aspergillosis [6?8]. A. flavus
seems also to be a prevalent species in India, Pakistan,
Qatar and Iran . An early study from Sudan 
showed that A. flavus represented 30% of all aspergilli
recovered from the air in June, when the weather is hot,
dry and dusty. Conversely, A. flavus was sporadically
recovered in winter months. Although A. flavus is very
prevalent in regions where the climate is dry and hot,
the presence of a humid and hot climate ? as occurs to
many parts of India ? may also predispose to A. flavus
infections. In addition, conditions of elevated humidity
and temperature have also been associated with A.
flavus contamination of crops and production of
In Europe, whilst A. flavus and A. niger were the
most frequent airborne aspergilli recovered in a study
performed in Barcelona , another investigation
conducted in Madrid showed A. fumigatus to be the
most prevalent species (54%) . This might be
explained by the existing climatic differences between
these two Spanish cities. Also interesting is the fact that
in the study performed in Madrid, A. niger and
A. flavus were found to be more heavily influenced by
meteorological parameters than A. fumigatus was .
Comparing the presence of Aspergillus species in the air
in London, Paris, Lyon and Marseille, Mallea et al. 
found that A. glaucus and A. versicolor predominate in
Southern France, whilst A. fumigatus represented
?35% of the isolates recovered from Paris and London.
Conidial size, surface and pigments
Aspergillus species produce conidia (asexual spores)
that can easily be dispersed in the soil and air. Uptake
of conidia by a susceptible host is usually the initial
event in Aspergillus diseases with alveolar macrophages
A. fumigatus conidia ranges from 2 to 3.5 mm, A. flavus
produces conidia ranging from 3 to 6 mm. This
difference in size is of great importance, allowing
A. fumigatus conidia to reach the pulmonary alveoli
much easier than do those of A. flavus. This probably
also explains why A. fumigatus is the main agent of
invasive pulmonary aspergillosis, while A. flavus is an
important aetiology of Aspergillus sinusitis and a
frequent cause of cutaneous and wound aspergillosis
. No data seems to exist on the importance of speed
of sedimentation of different sizes of Aspergillus spores,
which might also be important for the transmission of
In addition to conidial size, the outermost cell wall
layer of Aspergillus conidia may also be of importance.
The outer conidial surface contains rodlets that are
structures may confer resistance to extreme atmo-
spheric conditions and facilitate airborne dispersion
of Aspergillus conidia. Mutants lacking the gene RodA
? encoding the protein responsible for rodlet structure ?
display enhanced sensitivity to alveolar macrophage
killing . Accordingly, rodlets are believed to be
virulence factors [13?16]. However, deletion of the
RodA gene had no impact on virulence in a murine
model of pulmonary infection . Conidia from
DrodA mutants do not properly bind to proteins with
hydrophobic pockets, such as albumin or collagen ?
instead, binding occurs to other host proteins like
laminin and fibrinogen . Therefore, this mechanism
does not seem to be essential for Aspergillus patho-
Melanin is a large group of dense hydrophobic
pigments present in the cell wall of many fungi,
adjacent to the rodlet layer . The colour of the
pigment is usually dark brown or black, but many other
colours have also been observed . Melanin synthesis
has been linked to virulence in fungal organisms such
schenckii [21,22]. The pigment seems to confer protec-
tion to the conidia against environmental damage from
UV radiation. In addition, it seems to protect against
phagocytosis in vitro and in vivo . Melanin may also
reduce complement opsonization by ‘camouflaging’
binding sites, which for instance can reduce C3 ability
to bind conidia [19,24]. Mutant albine Aspergillus
strains have shown reduced virulence in comparison
to wild type strains in models of experimental asper-
gillosis, with albine conidia being more susceptible to
the oxidative mechanisms of monocytes and polymor-
phonuclear leukocytes [18,23?25]. Differences in mela-
nization between A. fumigatus and A. nidulans were
demonstrated by exposing these fungi to tricyclazole, a
fungicidal inhibitor of the THN-reductase enzyme,
involved in melanin synthesis via DHN-melanin path-
way . Exposure to tricyclazole resulted in inhibition
of conidial pigmentation in A. fumigatus but not
A. nidulans, showing that pigmentation involves differ-
ent pathways in these species. Studying melanisation in
A. fumigatus strains by immunofluorescence techni-
anti-melanin antibodies avidly attached to Aspergillus
conidia. The strength of this binding decreased with
conidial germination to become null after hyphae
– 2008 ISHAM, Medical Mycology
formation. These data suggest that melanin could be
more important as a facilitating factor for fungal
survival in the external environment than for virulence
in the host. Also again, no much data is there for A.
flavus. Since several non-pathogenic fungi are also
known to produce melanin, this pigment is probably
not essential for the occurrence of invasive fungal
diseases in humans .
Adhesion of Aspergillus conidia to the lung
The adhesion of Aspergillus conidia to proteins present
in the lung cell basal lamina is considered an important
initial step in the development of invasive aspergillosis.
Important proteins in this context include fibronectin
[27,28], laminin [28?30], type IV collagen [28,29],
fibrinogen, complement, albumin, and surfactant pro-
teins . In a comparison involving several Aspergillus
species, conidia of A. niger, A. fumigatus and A. flavus
were found to bind significantly better to fibrinogen
than A. terreus conidia . In another investigation
, A. fumigatus conidia were found to bind signifi-
cantly better to the basal lamina and fibronectin than
those of A. flavus. Studying the mechanisms involved in
conidial binding, the authors realized that negatively
charged carbohydrates occurring on the conidiospore
cell wall played a role in the adhesion of the conidia to
host basal lamina.
Alveolar macrophages represent the first line of defence
against pulmonary aspergillosis. Accordingly, therapy
with corticosteroids ? which may cause important
interference with the ability of macrophages to kill
resting conidia ? is a major risk factor for invasive
aspergillosis. Most in vitro studies of interactions
between macrophages and Aspergillus species have
been done on A. fumigatus [33?35] and very little is
known about A. flavus [36,37]. Previous studies re-
vealed that monocyte-derived human macrophages
exhibited lower phagocytic capacities against non-A.
fumigatus aspergilli, especially in A. nidulans and
A. niger, when compared with A. fumigatus. In addi-
tion, polymorphonuclear leukocytes induced signifi-
cantly less hyphal damage to both A. flavus and A.
nidulans than to A. fumigatus . Perkhofer et al. 
further investigated phagocytosis and intracellular kill-
ing for resting conidia of a wide range of Aspergillus
species by human monocytes-derived macrophages. No
differences between clinical and environmental isolates
were observed. Similar results were obtained for clinical
isolates of A. fumigatus and A. flavus, with mean killing
indexes at 120 minutes ranging from 13.7?77.8% and
14.2?42.2%, respectively. However, some marked iso-
late-related differences occurred.
Germination rate and thermotolerance
Araujo and Rodrigues  showed that germination
rates at 378C differed significantly for the most
common pathogenic Aspergillus species. Using the
same inoculum of Aspergillus spores in RPMI 1640
medium, A. fumigatus germinated faster than A. flavus,
which in turn germinated faster than A. niger. Inter-
esting results were also obtained when germination rate
was evaluated at different temperatures. The percentage
of germination markedly increased 3- to 10-fold for
both A. fumigatus and A. flavus when temperature was
increased from 208C to 308C, and again 2- to 3-fold
from 308C to 378C. However at 418C germination of
A. fumigatus was still enhanced, while germination of
A. flavus decreased by 45% (as compared with 378C).
The study suggested that temperature plays a crucial
role in selecting and promoting pathogenic species of
Aspergillus, with A. fumigatus being the species most
able to adapt to extreme changes in environmental
conditions. Nonetheless, it remains to be elucidated if
the same phenomenon also occurs in vivo. As demon-
strated in earlier studies , high conidial densities
were associated with lower in vitro germination rates.
In contrast to A. fumigatus, Neosartorya fischeri is
only rarely identified as a human pathogen. Since
phenotypic characterization has shown that both
A. fumigatus and N. fischeri can grow at 428C,
A. fumigatus may possess other genetic determinants
besides thermotolerance that allow it to establish a
successful in vivo infection .
Interactions with the endothelial cells
In a previously reported model of interaction of
A. fumigatus with primary cultures of human umbilical
vein endothelial cells it was observed that after 16 h of
interaction hyphae caused injury to the endothelial cell
monolayers . Further studies using two clinical
isolates of A. flavus (AFL8 and AFL24) using this
in vitro model showed that both isolates caused the
same amount of injury as observed for A. fumigatus
[Lopes-Bezerra, personal communication]. Although
invasion of the blood vessels is a key feature of invasive
aspergillosis, no comparative data was found for
A. flavus and A. fumigatus on the potential for causing
– 2008 ISHAM, Medical Mycology
Comparison of Aspergillus fumigatus and A. flavus
The role of albumin
Albumin accounts for around 50% of plasma proteins
and is involved in several physiological processes.
Rodrigues et al. investigated the effect of human
albumin upon conidial germination and hyphal devel-
opment of Aspergillus species . Although albumin
was shown to significantly promote germination of
A. fumigatus, the germination of both A. flavus and
A. niger was reduced in presence of albumin. A. flavus
germination was reduced by 20 and 25% in the presence
of 2 and 4% of human albumin, respectively. Similar
effects were obtained with the use of bovine albumin.
The formation of conidiophores and maturation of
A. fumigatus conidia were also faster in the presence of
Fungal secondary metabolites and toxines
Aspergillus species have been shown to produce several
secondary metabolites during invasive hyphal growth in
tissues . Many of such substances have been
identified as being important in the process of fungal
assimilation of nutrients from the host, and include
fungal enzymes and toxins. It remains however a
subject of debate whether any of these metabolites
actually represent a virulence factor. Differently from
what was described for other fungi such as C. neofor-
mans , no single gene virulence factors has been
identified for Aspergillus species. In addition, very little
is known about A. flavus, in comparison to its counter-
part A. fumigatus.
In order to cause invasive infections, filamentous
fungi require the activity of extracellular enzymes to
degrade the structural barriers in the host [44,45].
These enzymes include nucleases, oxidases, catalases,
phosphatases, peptidases and proteases, that are pro-
duced to degrade complex macromolecules in order to
provide nutrients for the fungus. Fungal proteases may
also induce local airway inflammation by activating
inflammatory pathways via epithelial cells .
Since elastin constitutes about 28% of lung tissue,
play a role in the pathogenesis of invasive aspergillosis.
Kothary et al. inoculated mice with elastase-producing
and non-producing environmental isolates of A. fumi-
gatus . While non-producer isolates caused no
destruction to the mice alveoli, isolates that produced
elastase killed animals within 48?96 h, which was
associated with substantial alveolar necrosis. Similar
elastase activity has been observed when clinical and
environmental isolates of A. fumigatus have shown to
produce similar amounts of elastase . In another
investigation, the in vitro elastolytic activity of A. flavus
was found to be much lower than of A. fumigatus .
A. flavus isolate producing exceptionally high levels of
Other proteases have been detected during Aspergillus
infection, including the alkaline serine protease, the
metalloprotease and an aspartic protease. The exact
importance of these enzymes in pathogenesis is un-
certain, and this subject has been recently reviewed .
For instance, deletion of the coding sequences was
associated with no phenotypic modification, and the
corresponding mutants retained their virulence in
murine infection models, with histopathological studies
showing similar extent of mycelial growth in the lungs
of parental and mutant strains [51?57]. The significance
of the recently identified sedolisins is also unclear .
The role of fungal enzymes involved in the propionyl-
CoA detoxification has recently been investigated for
A. fumigatus  and A. nidulans . When evaluated
in a steroid-immunosuppressed murine model of
A. fumigatus infection, a methylcitrate synthase mutant
displayed reduced virulence, suggesting that this pro-
tease may be involved in pathogenicity. Molecular
studies have been so far unable to identify a single
Aspergillus enzyme that is undoubtedly associated with
virulence in humans. Additionally, very little is known
about the importance of proteases in the pathogenesis
of A. flavus infections. Actually, most studies about
proteases secreted by Aspergillus of the flavus group
concerned A. oryzae and A. sojae, used in the food
Amongst the several secondary metabolites produced
by A. flavus are aflatoxins, the most toxic and potent
carcinogenic natural compounds ever characterized .
Aflatoxin may contaminate crops prior to harvest or
during storage, putting humans and other mammals
at risk. In addition, aflatoxins may also depress
phagocytosis, intracellular killing and spontaneous
superoxide production by macrophages . Experi-
mental animal models failed to establish a role for
aflatoxin as a virulence factor, since some virulent
strains of A. flavus do not produce aflatoxin [62,63].
Gliotoxin is one of the most abundant metabolites
produced by A. fumigatus during invasive hyphal
growth. This toxin exerts a broad spectrum of immu-
nosuppressive effects in vitro, including inhibition of
cytokine production, antigen presentation and produc-
tion of reactive oxygen species by macrophages, and
reduced cytotoxicity in T-cells . Low concentrations
of gliotoxin (0.2 mg/ml) may also impair respiratory
ciliary function, which is an important defence host
mechanism against aspergillosis . In parallel, other
– 2008 ISHAM, Medical Mycology
Aspergillus toxins like fumagillin and helvolic acid
require much higher concentrations to inhibit the cilia.
Gliotoxin has been detected in the blood of patients
with invasive aspergillosis , and mice administered
with gliotoxin showed marked immunosuppression
rending them at risk for invasive aspergillosis .
Therefore, gliotoxin has been proposed as a potential
virulence factor for A. fumigatus. However, a study
found no difference in the frequency or degree of
gliotoxin production when invasive aspergillosis pa-
tients were stratified by the EORTC criteria .
Similar results were observed for patients with proven
invasive aspergillosis or Aspergillus colonization, sug-
gesting that gliotoxin may have a limited role in the
pathogenicity of invasive aspergillosis, particularly in
infections caused by species other than A. fumigatus.
Data for gliotoxin production for A. flavus is scant,
and some experts will even argue that A. flavus does not
produce any gliotoxin at all. In a recent study, gliotoxin
production was detected in ?95% A. fumigatus strains
and in only 13% A. flavus strains . Similar results
were obtained in another investigation, in which 93%
and 4% of clinical isolates of A. fumigatus and A. flavus
were found to be gliotoxin-producers, respectively .
Not only gliotoxin production seems to be infrequent
for A. flavus isolates, but gliotoxin levels for A. flavus
are about 80-times lower when compared to what is
observed for A. fumigatus. For instance, in one
investigation  mean gliotoxin concentration in the
culture supernatants for clinical and environmental
strains of A. fumigatus ranged from 5-6 mg/ml, while
mean levels for A. flavus were 0.001 mg/ml only for
A. flavus. The impact of gliotoxin production might
also differ for A. fumigatus and A. flavus. While lack of
gliotoxin production in A. fumigatus significantly
reduces cytotoxicity on macrophage-like P388D1 cells
and CD8 T-cells, absence of gliotoxin does not seem to
influence cytotoxicity in A. flavus. Although high
concentrations of gliotoxin can also be detected in
infected lung tissues , no data seems to exist for
A. flavus infections.
Calcineurin is a Ca??-calmodulin-dependent phos-
phatase that is important in cell signalling . This
protein is a critical mediator of calcium signalling and
numerous cell stress responses in eukaryotic organisms,
including fungi. In A. fumigatus, calcineurin seems
necessary for filamentous growth . An A. fumigatus
mutant lacking the calcineurin A catalytic subunit
exhibits defective hyphal morphology resulting in
decreased filamentation. Another study revealed that
deletion of the calcineurin gene reduced A. fumigatus
virulence in mice . Also, calcineurin inhibitors such
as tacrolimus and cyclosporine have shown to create
gross and microscopic morphological changes in
A. fumigatus colonies . Although the calcineurin
gene seems important for A. fumigatus pathogenicity,
its role has not been clarified for infections caused by
other Aspergillus species.
Virulence in animal models
Animal models play a central role in identifying
virulence factors. Maybe the best evidence showing
higher virulence for A. flavus isolates in comparison to
A. fumigatus comes from studies involving mice. One
example is the classical study by Ford and Friedman,
published in 1967 . The study evaluated cumulative
mortality rates of normal mice inoculated intrave-
nously with 106viable spores from various Aspergillus
species. Although A. flavus killed all animals within
5 days of infection, only 40% of mice infected with
A. fumigatus were dead 20 days after the inoculation.
Curiously A. oryzae ? which has GRAS (‘generally
regarded as safe’) status ? proved to be as virulent as
A. flavus. None of the Aspergillus species studied
caused death when only 102spores were inoculated.
However, when a 104inoculum was used, A. flavus was
still able to kill 38% of animals. Immunosuppression
with cortisone, although greatly enhancing disease, was
not necessary to ensure infection in mice. In another
publication , normal mice were intravenously in-
oculated with 104Aspergillus spores. A. flavus and
A. fumigatus killed 35% and 25% of animals, respec-
tively, while A. terreus caused 5% mortality only.
More recently, studies in cyclophosphamide-immu-
nosuppressed CD-1 mice have demonstrated that a
much lower inoculum is required to kill animals when
these are intravenously infected with A. flavus spores, in
comparison to A. fumigatus [75?77]. While the LD90
(lethal dose killing 90% of animals) for A. flavus ranged
from 2.2?105to 2.6?105CFU/ml, a 4- to 50-fold
higher LD90occurred for A. fumigatus (1?106to 1.2?
107). For A. terreus, the LD90was about 40- to 100-fold
higher (1?107to 2?107) than the observed LD90for
A. flavus. It is noteworthy however that none of these
studies have directly compared virulence by testing
more than one Aspergillus species in the same experi-
ment. Fig. 1 shows the results of a study in which the
virulence of different Aspergillus species was compared
in an immunosuppressed mice model [Warn P, personal
communication]. While mean LD90(dose per gram) for
isolates of A. fumigatus was 9,566, LD90for A. flavus
was 1,440 (?7-fold less). A much higher inoculum was
required for A. niger and A. terreus, suggesting reduced
– 2008 ISHAM, Medical Mycology
Comparison of Aspergillus fumigatus and A. flavus
Similar results have been observed in a study in
which the invertebrate wax moth larvae were used as an
alternative host model of invasive aspergillosis [Slatter
J, personal communication]. As shown in Fig. 2,
survival rate for uninfected larvae was about 90% on
day 7. A lower virulence was observed for isolates of A.
terreus, in comparison to A. fumigatus. Similarly to the
studies involving mice, A. flavus demonstrated a higher
virulence in larvae, in comparison to the other Asper-
gillus species. All larvae infected by A. flavus died
within 2 days of infection.
One important limitation of the studies above is that
they all represent models of disseminated Aspergillus
infections. Although the data strongly suggests that
A. flavus is a more virulent species than A. fumigatus,
no direct comparison seems to exist using models of
inhaled infection. Intranasal inoculation mimics the
natural route of infection and would also be a more
appropriate route than intravenous inoculation [13,14].
As mentioned before, the bigger size of A. flavus
conidia may be an important factor limiting the ability
of these spores to reach the alveoli.
In order to establish a proper model of A. flavus
sinus or pulmonary infection, bigger animals such as
rabbits may be required, instead of mice or rat .
Evidence from clinical trials
No data regarding species-related mortality was pro-
vided in the two largest trials on invasive aspergillosis
[79,80]. This is probably due to the limited number of
patients included with non-A. fumigatus infections in
these studies. For instance, although 277 patients were
included in the voriconazole versus amphotericin B trial
, only seven patients had documented A. flavus
infection. In the AmBiLad trial  no details were
given regarding causative species. Therefore, no con-
clusion regarding differences in virulence among
Aspergillus species can be reached from these studies.
Due mainly to its conidia size, A. flavus is more likely to
be recovered from the upper respiratory tract than
A. fumigatus . A. flavus may be involved in all forms
of Aspergillus sinusitis, but there is a particular one that
deserves special attention: chronic granulomatous si-
nusitis. This is a curious syndrome of chronic slowly
progressive sinusitis associated with proptosis that has
been also called indolent fungal sinusitis and primary
paranasal granulomas [81,82]. Florid granulomatous
inflammation is the histological hallmark of this
condition, and virtually all cases are caused by
A. flavus. Again, almost all reports come from the
Sudan, Saudi Arabia, and the Indian subcontinent.
There are a limited number of reports in the USA,
which appear to almost exclusively affect African-
Americans . Patients tend to be immunocompetent
and involvement of the central nervous system fre-
Although A. fumigatus is the most frequent Aspergil-
lus organism causing allergic fungal sinusitis ,
A. flavus is a frequent aetiology in some geographic
areas, particularly the Middle East and India [84?88].
A. flavus is also not a frequent cause of sinuses fungal
balls (aspergillomas), with most reported cases occur-
ring in India, Sudan and other tropical countries .
Swiss mice. The y-axis shows the lethal dose required to kill 90% of
animals (LD90, dose per gram). All mice received 200 mg/kg of
cyclophosphamide 3 days before intravenous injection with Aspergil-
lus spores. Aspergillus species studied included A. fumigatus (strains
AF10, AF293, AF65, AF90, AF91, AF71, AF72, AF210, AF294,
and CEA10), A. flavus (AFL8 and AFL5). A. niger (AN6714), and A.
terreus (AT49). At least 10 animals were infected with each
Aspergillus isolate ? results on the graphic represent mean values.
Comparative virulence of Aspergillus species in outbred CD-1
Aspergillus species. Larvae were observed for 7 days at 378C. All
larvae received an inoculum of 2?106CFU/ml (2?104/larvae).
Survival rate for moth larvae infected with different
– 2008 ISHAM, Medical Mycology
As mentioned before, A. flavus is the second leading
cause of invasive pulmonary aspergillosis. Although
A. fumigatus causes the vast majorityof allergic bronch-
opulmonary aspergillosis (ABPA) cases, most of the
series in which A. flavus has also been implicated were
originated in India [89?91]. Interesting cases of ABPA
occurring as an occupational disease in individuals
without asthma have also been reported in Japan .
These were usually caused by A. oryzae and affected
workers involvedin the production of soybean products.
For unknown reasons, A. flavus rarely causes chronic
remains to be elucidated if A. flavus is less able than
A. fumigatus in causing chronic conditions such as
Cutaneous and wound infections
Most cases of cutaneous aspergillosis involve A. flavus
. The same is also true for tongue aspergillosis [94,95],
which tends to affect neutropenic patients with intense
mucositis or oral ulcers. In a recent review of post-
operative aspergillosis, A. flavus was identified in 41.2%
of wound aspergillosis cases confirmed by culture .
In some reports, infections havebeen associatedwith the
dissemination of A. flavus spores within the surgical
room. A. flavus is also the main cause of Aspergillus
osteomyelitis following trauma [97?99].
Fungal keratitis occurs predominantly in tropical and
warm climates. At least 80% of Aspergillus keratitis
cases are associated with A. flavus . The major
predisposing condition to A. flavus keratitis is trauma,
generally with plant material .
Outbreaks of aspergillosis involving the skin, oral
mucosa or subcutaneous tissues are more frequently
associated with A. flavus than any other Aspergillus
A. fumigatus, the evidence for this assumption is based
mainly on experimental models of disseminated infec-
tion. Comparative studies in which animals are primar-
ily infected via the respiratory tract are lacking and
required. In addition, the available data shows highly
variable results depending on the Aspergillus isolate
studied, suggesting intra-species variation in virulence.
It seems however that A. fumigatus is more able than
A. flavus to adapt to extreme changes in environmental
conditions, which includes the human body.
The size of A. flavus conidia is a very important
determinant of the clinical presentations of aspergillo-
sis caused by this species. Accordingly, A. flavus is
particularly significant in infections involving the
paranasal sinuses, skin, mucosas and the eyes. The
prevalence of A. flavus in the environment depends
greatly on climate conditions. It remains to be seen if
the phenomenon of global warming will lead to an
increase in A. flavus infections in the clinical practice.
I would like to thank Dr Peter Warn and Joanne
Slatter, who kindly provided me with their data on
animal and larvae models. I am also in debt with Dr
Kwon-Chung, for giving helpful expert advice and Dr.
Lopes-Bezerra, for her data on endethelial cells.
Declaration of interest: The author reports no conflicts
of interest. The author alone is responsible for the
content and writing of the paper.
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