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Rasamsonia argillacea species

Review
Future Microbiology
complex: taxonomy, pathogenesis
and clinical relevance
Sandrine Giraud*1, Loïc Favennec2, Marie-Elisabeth Bougnoux3
& Jean-Philippe Bouchara1,4
1
LUNAM Université, Université d’Angers, Groupe d’Etude des Interactions Hôte–Pathogène, UPRES-EA 3142,
49933 Angers cédex 9, France
2
Université de Rouen, Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Rouen,
France
3
Université Paris Descartes, AP-HP, Hôpital Necker-Enfants malades, Service de Microbiologie, Paris, France
4
Laboratoire de Parasitologie–Mycologie, Centre Hospitalier Universitaire, Angers, France
*Author for correspondence: n Tel.: +33 2 44 68 83 64 n Fax: +33 2 41 22 67 09 n sandrine.giraud@univ-angers.fr

Since 2010, colonizations/infections by Rasamsonia argillacea species complex,

previously known as Geosmithia argillacea, have been regularly reported in
literature. We reviewed all available cases focusing on pathogenesis and clinical
relevance. The number of cases may be underestimated, as these fungi are
frequently misidentified as Penicillium or Paecilomyces species. Major underlying
conditions that predispose for infections by the R. argillacea species complex
include cystic fibrosis (CF) and chronic granulomatous disease (CGD). While the
pathogenic role of the colonization of CF lungs is still under debate, these molds
are the causative agent of pneumonia and/or invasive infections in CGD patients.
Given their thermotolerance and their resistance to various antifungals, especially
the azole drugs, a special attention should be paid to the chronic colonization
of the airways by these fungi in CF and CGD patients.

Before the end of the 1990s, the Rasamsonia
argillacea species complex, previously known as
Geosmithia argillacea, was not reported in the
medical literature, possibly owing to the dif-
ficulty in identifying it properly. Indeed, these
thermotolerant molds are frequently misidenti-
fied as Penicillium or Paecilomyces species. Since
2010, this fungus has been isolated regularly
in sputum samples recovered from European
patients with cystic fibrosis (CF) and described
as the causative agent of disseminated infections
in patients with chronic granulomatous disease
(CGD). This review will focus on taxonomic
updates within the Geosmithia genus that led
to the creation of the new genus Rasamsonia.
The pathogenesis of these fungi and the clinical
relevance of their isolation will also be discussed.
Taxonomy & identification
G. argillacea was initially described under the
name Penicillium argillaceum by Stolk et al. in
1967 as a new thermotolerant Penicillium species
[1]. In 1979, Pitt proposed the genus Geosmithia
to accommodate isolates previously known as
Penicillium species, but producing conidia that
forms lineages in the Hypocreales and Eurotia-
les [3]. Geosmithia lavendula, the type species of
Geosmithia, shows affiliation to the Hypocre-
ales and is related to Acremonium alternatum,
the type species of Acremonium. Most species
belonging to this lineage are associated with
the galleries of phloem-feeding bark beetles
[4–7]. The Eurotiales lineage is divided into two
subgroups based on their teleomorph species:
the Talaromyces-producing Geosmithia species,
which comprise G. argillacea (of which the
sexual state is Talaromyces eburneus [8]); and the
Chromocleista malachitea-producing Geosmithia
species, the Eupenicillium crustaceum-producing
Penicillium species and the anamorph state of
Talaromyces avellaneus, Merimbla ingelheimense.
These molecular data were also supported by
differences in the major ubiquinone system, as
well as in the polysaccharide composition of the Keywords
cell wall [9]. More recently, this taxonomy was n chronic granulomatous
revisited by Houbraken et al. [10]. In this study, disease n cystic fibrosis
molecular characterization of thermotolerant n filamentous fungi
n Geosmithia argillacea
or thermophilic members of the family Tricho-
n German shepherd dog
comaceae including G. argillacea, Talaromyces n graft-versus-host disease
emersonii and Talaromyces byssochlamydoides n Rasamsonia argillacea

were not typically green [2]. Microscopically,
Geosmithia was also distinguished by rough-
walled metulae and phialides. Phylogenetic
analysis based on 18S ribosomal DNA sequences
demonstrated that this genus is polyphyletic and
was conducted using partial RPB2 (RNA poly- species complex
n thermotolerance
merase II gene), Tsr1 (putative ribosome bio-
genesis protein) and Cct8 (putative chaperonin
complex component TCP-1) gene sequences, and
the results were combined with observations of part of

10.2217/FMB.13.63 © 2013 Future Medicine Ltd Future Microbiol. (2013) 8(8), 967–978 ISSN 1746-0913 967
 Review Giraud, Favennec, Bougnoux & Bouchara
morphological and physiological features. The
genus Rasamsonia was created in honor of RA
Samson for his 65th birthday and his 40 years
of service at the CBS-KNAW Fungal Biodiver-
sity Center (Utrecht, The Netherlands). In the
Nomenclature section of the 18th International
Botanical Congress in Melbourne in 2011, the
proposal to revise article 59 of the International
Code of Botanical Nomenclature was accepted
and the principle of ‘one fungus: one name’
was established [11]. In light of this decision, a
single name was proposed for Rasamsonia. It
resembles Paecilomyces and comprises thermo-
tolerant species with olive-brown conidia and
ascomata, but more regularly branched conid-
iophores with distinctly rough-walled stipes.
The Eurotialean species G. argillacea, Geosmi-
thia cyclindrospora and Geosmithia eburnea were
transferred to this genus. New combinations
for T. byssochlamydoides and T. emersonii were
made in this genus and a new species named
Rasamsonia brevistipitata was proposed. More-
over, Su et al. characterized an additional species,
Rasamsonia composticola, isolated from compost
in China and related to Rasamsonia emersonii
and Rasamsonia byssochlamydoides [12]. Finally,
the diversity among a set of R. argillacea isolates
was studied using several gene sequences (inter-
nal transcribed spacer regions, partial b-tubulin
and calmodulin genes) associated with morpho-
logical characteristics and revealed four species
into the R. argillacea complex, that is. R. argil-
lacea sensu stricto, Rasamsonia eburnea and two
new species, Rasamsonia piperina and Rasamso-
nia aegroticola [13]. Figure 1 illustrates the various
successive refinements in the taxonomy of the
R. argillacea species complex.
Currently the genus Rasamsonia comprises
nine species: R. argillacea (F igur es 2A & 2C),
R. brevistipitata, R. byssochlamydoides, R. compos-
ticola, R. cyclindrospora, R. eburnea, R. emersonii,
R. piperina and R. aegroticola (Figures 2B & 2D), and
their phenotypic characteristics are summarized
in Table 1. Correct phenotypic identification by
routine laboratories is difficult. Recently, Del
Chierico et al. designed a matrix-assisted laser
desorption/ionization-TOF mass spectrometry
(MS)-based assay to identify filamentous fungi
from clinical origins [14]. Twenty species were
used, and specific MS fingerprints were provided
for G. argillacea after 120 h of culture at 30°C
on Sabouraud agar medium. The analytical
performance of morphotyping (MT) and MS
phenotyping were compared by concordance
analysis against genotyping (GT; based mainly
on 28S rDNA sequencing) and promising results
968 Future Microbiol. (2013) 8(8)
were obtained by MS identification. Among the
ten G. argillacea isolates studied, nine showed
concordant MT versus GT identification and
seven showed concordant MS phenotyping ver-
sus GT identification. One isolate was misiden-
tified by MT and three could not be identified
by MS phenotyping. However, this study was
performed on the basis of the old nomenclature,
and a database extension is necessary in light of
the recent taxonomic updates. Consequently, to
date, only internal transcribed spacer sequencing
allows the correct identification of species within
the Rasamsonia genus.
Pathogenesis
A computerized search of the literature was made
for cases of infections caused by the R. argillacea
species complex with the terms ‘G. argillacea’
and ‘T. eburneus’ on several databases (MED-
LINE database, National Library of Medi-
cine, Bethesda, MD, USA; Web of knowledge
database, Thomson Reuters, NY, USA). Other
search terms were added referring to prior or new
nomenclatures, in other words ‘P. argillaceum’
or ‘Rasamsonia’.
The first reported case of infection due to
the R. argillacea species complex was published
in 2009, concerning an infection in a German
shepherd dog [15]. Since that date, these fungi
have been identified regularly, and 80 cases were
reported in the literature [10,15–23] or in con-
gresses [24–26]. However, records of isolation were
available for only 59 of them (Figure 3). A total of
86% of these isolations have been obtained since
2005. Prior misidentifications that are frequently
reported and corrected using molecular methods
clearly indicate that the number of cases may be
underestimated due to the culture-resemblance
of species of the R. argillacea complex to Peni-
cillium or Paecilomyces species. The increased
attention paid to fungal infections, together
with improvement of the detection methods
for fungi and a more frequent use of molecular-
based techniques (especially DNA sequencing),
undoubtedly accounts for part of this increasing
occurrence. However, although the procedure
used for mycological examination of sputum
samples has not changed over the past 6 years
in our hospital laboratories (Angers and Rouen),
we have observed a growing number of patients
with CF colonized by species of the R. argillacea
complex since 2006. Nevertheless, we cannot
confirm a true emergence of these fungi because
changes in clinical practice (more aggressive
physical therapy and therapeutic intervention)
may have head to a greater selection pressure.
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 Rasamsonia argillacea species complex: taxonomy, pathogenesis & clinical relevance
Indeed, for some of the cases reported in the
literature, R. argillacea infection or colonization
occurred while patients were being treated with
azole antifungals [16,19,20].
Portal of entry
Although in one case of atopic eczema a cutane-
ous infection may be suspected, almost all the
R. argillacea sensu lato isolates reported in the
literature were recovered from sputum samples,
bronchial aspirates or lung biopsies. Because
of this frequency in respiratory specimens, it
is most likely that the fungus enters the host
through inhalation of conidia. Bone or CNS
involvement occurs secondary to colonization
of the respiratory tract [19,20].
Predisposing factors & underlying
conditions
The most frequent underlying conditions that
have been reported are CF (70%) and CDG
(11%; Figure 4). The thickening of the bronchial
mucus in the CF airways and the inability of
CGD patients to generate microbicidal reactive
oxygen species predispose CF and CGD patients
to infections due to filamentous fungi, especially
Aspergillus fumigatus, which is the major cause of
morbidity and mortality in both contexts.
Approximately 10% of reported patients
showed immunosuppressive conditions such
as bone marrow or solid organ transplantation.
Moreover, two animal cases were reported,
occurring in German shepherd dogs [10,15], ani-
mals that are highly suspected of a breed-related
immunodeficiency, although study conducted
by Day et al. failed to identify the specific
defect [27].
Geographical distribution
Regarding geographical features, all reports in
the CF context were from Europe (France, the
UK, Italy, Germany and The Netherlands).
The other cases were distributed similarly in
Europe and USA, with occasional cases from
Asia (especially Korea).
Pathogenesis according to the
taxonomic update
In the taxonomic study leading to revision of
the Geosmithia genus and reassignment of some
species to the new genus Rasamsonia, Houbraken
et al. conducted a retrospective analysis that
identified, in several cases, the species involved
within the R. argillacea complex [13]. A similar
work was performed here on two additional pub-
lished studies. Jang et al. isolated R. argillacea
future science group
Review
Penicillium argillaceum
Geosmithia argillacea
(sexual state: Talaromyces eburneus)
Rasamsonia argillacea
Rasamsonia argillacea
Rasamsonia eburnea
Rasamsonia piperina
Rasamsonia aegroticola
Figure 1. Taxonomic changes in the
Rasamsonia argillacea species complex.
Solid arrows indicate changes in genus name
and the dashed arrow indicates the
identification of novel species based on
molecular analysis associated with
morphological characteristics.
from two clinical samples [22]. The internal tran-
scribed spacer sequences deposited in Genbank
were used for precise species identification. The
isolate recovered from a transtracheal aspirate
from a patient presenting with an acute lympho-
blastic leukemia and an influenza H1N1 infec-
tion (Genbank accession number GU165726.1)
contained R. argillacea sensu stricto and the other
recovered from a lung biopsy from a patient with
chronic cavitary aspergillosis (Genbank acces-
sion number HQ246728.1) was assigned to
R. aegroticola. Similarly, results of the BLAST
searches reported by Doyon et al. suggest that the
only case of infection in an immunocompetent
patient is due to R. piperina [21]. Consequently,
reidentification was performed for 24 cases, and
the results are summarized in Table 2. Similar pat-
terns were found to be associated with CF and
CGD. In both clinical contexts, R. aegroticola
is the most frequent species of the complex, fol-
lowed by R. argillacea and R. piperina. R. ebur-
nea was not recovered in these contexts, but this
fungus was recovered from two other clinical
samples. However, among all clinical reports
until now, the number of cases that could be
analyzed limits the generalizability of these
results. Further survey is required for a better
understanding of the epidemiology of species of
the R. argillacea complex.
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 Review Giraud, Favennec, Bougnoux & Bouchara
Figure 2. Morphological features of Rasamsonia argillacea and Rasamsonia aegroticola.
(A & C) Rasamsonia argillacea and (B & D) Rasamsonia aegroticola. (A & B) Seven‑day-old cultures
at 37°C on yeast extract–peptone–dextrose–agar medium. (C & D) Microscopic examination with
lactic blue stain.
Scale bars: 10 µm.
In vitro antifungal drug susceptibility
So far, no data have been made available regard-
ing the in vitro antifungal susceptibility of
R. composticola. The susceptibility profile for
R. brevistipitata differs from that of the other
Rasamsonia species, with low minimum inhibitory
or effective concentrations (<0.5 µg/ml) for all the
drugs tested, including amphotericin B, itracona-
zole, posaconazole, voriconazole and caspofungin
[13]. However, only two isolates were tested for this
species, and further analysis using a larger set of
isolates is required to confirm these results.
Regarding the other Rasamsonia species, vori-
conazole showed no efficacy since most of the
isolates were not inhibited at a concentration of
16 µg/ml. Susceptibilities to amphotericin B,
posaconazole and itraconazole were variable.
Echinocandins were the most active antifungal
class against R. argillacea sensu lato and the related
species R. cyclindrospora [16–21,23]. Data were
reported mainly for caspofungin. However, when
micafungin and anidulafungin were tested, their
minimum effective concentration values always
were lower than those obtained for caspofungin.
Few isolates were analyzed regarding terbinafine,
970 Future Microbiol. (2013) 8(8)
which showed a high efficacy. This susceptibility
profile differs from that observed for Paecilomy-
ces species, which exhibits variable susceptibility
to echinocandins and a high susceptibility to
posaconazole [13]. This demonstrates that correct
species identification is required for an appropriate
antifungal therapy.
Moreover, in a recent study, the in vitro antifun-
gal activity of colistin was investigated as a single
agent or in combination therapy with voricon-
azole, amphotericin B or caspofungin [28]. Colis-
tin is a cationic antibiotic that became available
for clinical use in the 1960s, but its use was dis-
continued in favor of less-toxic antibiotics in the
1970s due to the common occurrence of severe
side effects (nephrotoxicity and neurotoxicity) [29].
The increasing occurrence of multidrug resistance
in Gram-negative bacteria, especially P. aerugi-
nosa, Acinetobacter baumannii and Klebsiella pneu-
moniae as well as the limited therapeutic options
led physicians to reconsider the clinical use of
colistin [30–32]. Nowadays, colistin is an extremely
important antibiotic for the treatment of Pseudo-
monas infections in CF patients [33,34]. Interest-
ingly, a study from Schemuth et al. demonstrated
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 Rasamsonia argillacea species complex: taxonomy, pathogenesis & clinical relevance Review

that colistin also exhibited an antifungal activ-
ity against R. argillacea sensu lato with indiffer-
ent effect when combined with voriconazole or
amphotericin B [28]. However, a combination of
colistin with caspofungin exhibited nearly 90%
antagonistic effects, indicating that a concomitant
administration of these two drugs is less effective
in the treatment of R. argillacea infections [28].
Clinical relevance
Given the limited number of cases in other con-
texts (Figure 3), this review will focus on the two
main predisposing factors, including CGD and
CF, regarding the clinical relevance of coloni-
zations/infections caused by the R. argillacea
species complex.
Chronic granulomatous disease
CGD is a heterogenous group of inherited dis-
eases characterized by various genetic disorders
of the NADPH oxidase system. This system
consists of several components: the cytochrome
b 558 heterodimer located in the membrane,
which comprises the gp91phox and p22phox units,
and three other subunits (p67phox, p47phox and
p40phox), which are cytosolic. Following cellu-
lar activation, these three soluble components,
together with the GTPase protein Rac, bind to
the cytochrome b558 heterodimer. This results in
flavocytochrome activation, which catalyzes the
transfer of electrons from NADPH to oxygen
and induces the formation of superoxide anions
in the phagolysosome. In this compartment,
reactions involving superoxide dismutase or
catalase can produce H2O2 or H2O, respectively.
Various molecular subtypes of CGD exist based
on the mutated subunits of the NADPH oxidase
involved. X-linked CGD arises due to mutations
in the gp91phox gene and is responsible for 65%
of cases. The remaining 35% of cases result from

Table 1. Characteristics of Rasamsonia species.

Species Growth on CYA Shape and size of conidia† Ascomata/ Branching pattern Ref.
(7 days, 37°C) ascospores conidiophores
Rasamsonia 30–40 mm Cylindrical or ovoid, 3.5–4.5 Absent Regularly branched, [10]
argillacea sensu (minimum: 3.0; maximum: 5.0) predominantly bi- or ter-
stricto‡ × 1.5–2.0 (maximum: 2.3) µm verticillate, occasionally
monoverticillate
Rasamsonia 30–40 mm Variable, predominantly ellipsoidal Occasionally Regularly branched, mono-, [10]
eburnea‡  or ovoid but also cylindrical, present, maturing bi- and ter-verticillate
2.5–3.5 (maximum: 4) slowly,
× 1.8–2.5 µm 4–5 × 4–4.5 µm
Rasamsonia 25–40 mm Variable; predominantly cylindrical Absent Often subterminally [13]
aegroticola‡ or ellipsoidal, 2.5–3.5 × 1.8–2.5 µm branched, biverticillate
Rasamsonia 15–25 mm Ellipsoidal or cyclindrical, Absent Often subterminally [13]
piperina‡ 2.0–3.5 × 1.7–2.5 µm branched, biverticillate
Rasamsonia 11–17 mm Ellipsoidal or ovoid, 2.5–3.0 Absent Regularly branched, [10]
brevistipitata (minimum: 2.0; maximum: 3.5) monoverticillate or
× 1.7–2.1 µm biverticillate
Rasamsonia 19–27 mm Cylindrical, 4–8 × 1–2.5 µm Present, usually Irregularly branched, ter- or [10]
byssochlamydoides maturing within quarter-verticillate
7 days,
3.7–4.5 × 3.5–4 µm
Rasamsonia 5–10 mm Cylindrical, 4.0–5.0 × 1.6–2.1 µm Absent Regularly brenched, [10]
cyclindrospora predominantly biverticillate,
occasionally terverticillate or
simple
Rasamsonia 18–30 mm Cylindrical, 3.5–4.5 (maximum: 5.0) Present, usually Regularly branched, bi- or [10]
emersonii × 1.5–3.0 µm maturing within ter-verticillate
7 days,
3.5–4 × 4–4.5 µm
Rasamsonia 25–40 mm Cylindrical, hyaline, slightly larger at Present, 2–3.8 µm Regularly branched, bi- or [12]
composticola one end, 3–8.75 × 1.5–3.75 µm ter-verticillate
The numbers in brackets represent the minimum and/or maximum sizes that can sometimes be observed.
†

Species belonging to the Rasamsonia argillacea species complex.

‡

CYA: Czapek yeast extract agar.

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 Review Giraud, Favennec, Bougnoux & Bouchara
35
30
30
25
21
20
Cases (n)
15
10
4 apy. Surgery was required for five patients. Such
5
2 2
0 therapy resembles that due to other filamentous
1990–1994 1995–1999 2000–2004 2005–2009 2010–2012
Date of first isolation
Figure 3. Distribution of the cases of Rasamsonia argillacea
colonization/infection by 5-year periods. All the cases of Rasamsonia argillacea
colonizations/infections (80) reported in the medical literature or in congresses
were analyzed. Records of isolation were available for 59 of them and a
classification of these cases by 5-year periods was performed.
mutations in the other components of NADPH
oxidase (mainly p22phox, and to a lesser extent
p67phox and p47phox) and represent the auto­somal
recessive CGD [35]. Indeed, the inability to gen-
erate superoxide anions leads to the defective
killing of certain pathogenic microorganisms,
such as Staphylococcus aureus and Pseudomonas,
Nocardia or Aspergillus species [36,37]. There-
fore, the most common clinical manifestations
include life-threatening infections together with
granulomatous complications and inflammatory
bowel diseases. Ahlin et al. showed that patients
with X-linked CGD had more infections than
their autosomal recessive counterparts [38].
Typical infections include purulent bacterial
infections such as pneumonia and sinusitis, or
necrotizing fungal infections of deep tissues or
bone [35,39,40]. These invasive fungal infections
occur in up to 43% of the patients over time
[41]. Aspergillus species, especially A. fumigatus
and A. nidulans, are the most frequent fungi
encountered in this context and the major cause
of morbidity and mortality [42,43]. However,
other less-common fungi such as Pneumocys-
tis jirovecii [44,45], Cryptococcus neoformans [46],
Trichosporon inkin [47] and Paecilomyces spe-
cies are less frequently identified. Since 2000,
R. argillacea infections were reported in nine
CGD patients [19,20]. Eight of them suffered
972 Future Microbiol. (2013) 8(8)
from severe protracted infections. The most
common clinical presentation was pneumo-
nia (eight out of nine). The last case corre-
sponded to an invasive infection in an alloge-
neic peripheral blood stem cell transplantation
using a matched unrelated donor, with acute
grade II graft-versus-host disease. For four of
these patients, R. argillacea infections occurred
while they were receiving long-term antifun-
gal prophylaxis (mainly based on azole drugs).
Pulmonary infiltrations rapidly extended across
tissue planes from lungs to adjacent ribs and
chest wall in four patients and involved proven
(for one patient) or presumed (for two patients)
cerebral dissemination, despite antifungal ther-
a clinical presentation with an aggressive dis-
ease pattern that was refractory to antifungal
fungi in CGD. Indeed, A. nidulans or Neosar-
torya udagawae were previously described as
being responsible for invasive aspergillosis in
CGD patients, and these infections spread in a
contiguous manner and could result in invasion
of adjacent bone [48–50].
Cystic fibrosis
CF is the most common autosomal recessive
disorder in the European Caucasian popula-
tion [51]. In the respiratory tract of CF patients,
defects in mucociliary clearance and thickening
of the bronchial mucus resulting from muta-
tions in the gene encoding the CF transmem-
brane conductance regulator (CFTR) allow the
entrapment of airborne bacteria and fungal
spores and provide a suitable environment for
growth of microorganisms [52]. The respiratory
tract of patients, therefore, is often colonized
by microorganisms. This colonization of the
airways usually is not associated with signs of
clinical or functional deterioration, perhaps
because of more aggressive therapeutic inter-
vention keeping the patients asymptomatic or
weakly symptomatic. Nevertheless, this airway
colonization may sometimes lead to true respi-
ratory infections, which are the major cause of
morbidity and mortality in CF patients [53]. The
role of bacteria such as S. aureus or P. aerugi-
nosa in acute pulmonary exacerbations and
CF lung deterioration is well-established, but
fungal colonization of the airways and possible
subsequent respiratory infections are increas-
ingly gaining attention [54]. Most studies have
focused on A. fumigatus and allergic broncho-
pulmonary aspergillosis, the prevalence of
which is 1–15% [55]. However, the fungal biota
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 Rasamsonia argillacea species complex: taxonomy, pathogenesis & clinical relevance
colonizing the CF lung is largely more complex
and includes various non-Aspergillus filamen-
tous fungi such as some species of the Scedo-
sporium genus or Exophiala dermatitidis [56,57].
Nevertheless, the pathogenic role of these fungi
in progression of the CF lung disease remains
poorly documented.
In 1999, we reported the first case of airway
colonization by R. argillacea sensu lato. Initially,
the fungus was identified as Penicillium emer-
sonii on the basis of its morphological features
[58], and it was later reassigned to the Rasamsonia
genus by internal transcribed spacer sequenc-
ing together with eight other cases diagnosed
between 1999 and 2009 in the CF context [16].
At the same time, Barton et al. also reported
eight cases in UK [17]. Since this date, this fun-
gus was isolated regularly from sputum samples
from CF patients in several European countries
including Germany, The Netherlands, Austria,
France and Italy. However, only few identifica-
tions or reidentifications were performed taking
into account the recent taxonomic updates [13].
The results of this are summarized on Table  2
and show that only three species of the complex,
R. aegroticola, R. argillacea and R. piperina, were
encountered as causal agents of airway coloniza-
tion. To date, R. eburnea has not been found in
the CF context.
In our previous study, sequential isolates
(i.e., successive samples collected from the
same patient) were identical when submit-
ted to a multigene sequence typing analysis
[16]. This suggests that species of the R. argil-
lacea complex may chronically colonize the
airways of CF patients. This result was con-
firmed, at least for R. aegroticola, in a Dutch
CF patient [13]. This is in agreement with
data on A. fumigatus and S. apiospermum spe-
cies complex, the most common filamentous
fungi encountered in CF [59–61]. The authors
have previously reported that colonization by
R. argillacea always occurred subsequently to
infections by various bacteria [16]. All but one
of our nine patients colonized by R. argillacea
were also chronically colonized by S. aureus [16].
However, for almost all the patients, no clear
relationships were established with clinical sta-
tus or lung deterioration. Never­t heless, the fact
that this fungus may cause invasive infections in
an immunocompetent host or in patients with
CGD or graft-versus-host disease suggests that
one may be cautious in patients undergoing
lung transplantation. Additionally, R. argilla-
cea is not a commensal of the airways and, as
with other filamentous fungi like A. fumigatus
future science group
Review
or S. apiospermum, colonization of the respira-
tory tract by this fungus may contribute to the
exacerbation of the inflammatory reaction and
therefore to the progressive deterioration of the
lung function. It could also form mixed bio-
films with bacteria. Indeed, most if not all bac-
teria and fungi are capable of forming biofilms,
which could be defined as structured consortia
of microorganisms embedded in a self-produced
polymer matrix. Biofilm formation is associated
with a lowered susceptibility to anti-infective
drugs [62,63]. Gradients of nutrients and oxygen
that occur from the top to the bottom of bio-
films and some secondary metabolites produced
by microorganisms may affect the expression
of genes encoding some virulence factors [64].
Several studies demonstrate that P. aeruginosa
influences C. albicans and A. fumigatus biofilm
formation in the CF context [65–67]. In addition,
recently, Marguet et al. [23] reported a case pro-
viding the first clue for the clinical relevance of
the airway colonization by R. argillacea. In this
patient, R. argillacea was considered as the likely
cause of recurrent asthma-like symptoms. Each
episode of isolation of the fungus was associ-
ated with a dramatic decrease in FEV-1 pre-
dicted value, and its normalization following
antifungal therapy, together with unchanged
80
70
60
50
Cases (%)
40
30
20
10
0
Transplantation
Clinical fibrosis
Chronic granulomatous disease
Acute lymphoblastic leukemia
Atopic eczema
Other causes of immunodeficiency
Immunocompetent hosts
Unspecified context
Animal cases
Clinical context
Figure 4. Predisposing factors for Rasamsonia argillacea
colonizations/infections.
www.futuremedicine.com 973
 Review Giraud, Favennec, Bougnoux & Bouchara
Table 2. Distribution of species of the Rasamsonia argillacea complex according to
the underlying disease.
Species Cystic fibrosis Chronic granulomatous
disease
Rasamsonia aegroticola 5 5
Rasamsonia argillacea 3 2
Rasamsonia eburnea 0 0
Rasamsonia piperina 2 1
Values correspond to the number of cases according to this review and [13].
bacteria colonization before and during the
period of colonization by R. argillacea, was
consistent with a pathogenic role of the fun-
gus. The patient was successively treated with
posaconazole, voriconazole and caspofungin,
which resulted in short-term improvement of
the patient, albeit without eradication of the
fungus. Finally, the patient was treated with
prolonged high-dosage micafungin, which led
to both clinical and functional improvement of
the patient and eradication of the fungus. Anal-
ysis of the microbial community in the lungs of
CF patients in the future should allow elucida-
tion of the role of R. argillacea and to clarify the
epidemiological link with the CFTR genotype.
Indeed, approximately 65% of all reported cases
with known CFTR genotype were diagnosed in
patients homozygous for the F508del mutation,
and all patients carried at least one allele with
this mutation. Moreover, based on the cases
reported by the authors [16] and Barton et al. [17],
the mean age of the patients at date of first iso-
lation of the fungus was 18.11 years. However,
two subgroups can be distinguished, since the
mean age was 13.5 years for F508del-homozy-
gous patients (range 6–24 years) and 27.2 years
for heterozygous patients (range 8–48 years).
This is in agreement with the more aggressive
pattern of the disease in patients homozygous
for this mutation.
Conclusion
Although uncommon in clinical practice, species
of the R. argillacea complex are being increas-
ingly reported, mainly associated with CGD and
CF. An early and comprehensive microbiology
workup is essential, especially in CGD patients,
to correctly identify these pathogens. Species
of the R. argillacea complex are frequently mis­
diagnosed. When Paecilomyces variotii and Peni-
cillium emersonii are identified based on mor-
phological features, molecular methods should
be used to exclude species of the R. argillacea
complex, in order to guide clinicians in the use of
974 Future Microbiol. (2013) 8(8)
Other underlying
diseases
0
1
2
3
more appropriate antifungal therapy. Moreover,
given their thermotolerance and their capabil-
ity to disseminate, one should be cautious with
patients colonized by these fungi when lung
transplantation is required.
Research challenges & future
perspective
As mentioned above, R. argillacea infec-
tions have been increasingly reported during
the past decade. This may be the result of
improved methods of detection and identifica-
tion of fungi. Nowadays, correct identification
based exclusively on morphological features is
becoming increasingly difficult and molecu-
lar methods, especially DNA sequencing, are
frequently used for identification [68–70]. The
resulting increase of available sequences in the
database accounts at least for part of this grow-
ing occurrence. However, other parameters may
be involved, since an increasing incidence of
these fungi was also found in our CF centers
over the past few years without any changes
in the procedures used for mycological exami-
nation of sputum samples. Global warming
is likely to have impacts on human health via
changes on aeroallergens and related diseases,
including mold spores. Most works on the
impact of climate changes on aeroallergens have
been performed on plants and pollens [71–73].
Only a few studies have examined their poten-
tial effects on the fungal community. Corden
and Millington investigated long-term trends
in seasonal variations in Alternaria spores con-
centration and start dates in Derby (UK) from
1970 to 1998 [74]. They demonstrated a trend
for a longer Alternaria season associated with
an earlier seasonal start (from late June at the
beginning of the study to early June at the end).
Moreover, the seasonal Alternaria spore con-
centration showed a distinct upward trend over
this period (at first gradually and then mark-
edly from 1992). Similarly, in a review about
disease risk linked to global warming, Harvell
future science group
 Rasamsonia argillacea species complex: taxonomy, pathogenesis & clinical relevance Review

et al. reported numerous climate/fungi rela-
tionships of importance mainly in plants but
also in wildlife and marine diseases [75]. The
potential impacts of climate changes on devel-
opment and survival rates of thermotolerant
fungi such as the R. argillacea species complex,
remain to be investigated. Unfortunately, due
to the recent description of these fungi, no prior
data are available, and evolution of their geo-
graphic distribution in the environment should
be followed up over the next few years.
Another important research challenge asso-
ciated with R. argillacea infections is the ori-
gin of contamination of the patients. Indeed,
only few data about the ecology of species of
the R. argillacea complex are available. While
R. aegroticola has been isolated exclusively from
clinical samples to date [13], R. argillacea sensu
stricto is a common species in the environment.
It was isolated from mine tips and indoor air,
and was also described as a contaminating agent
of pasteurized pineapple juice in the beverage
industry [8]. Rasamsonia eburnea was identified
from Taiwanese soil [76] and R. piperina was iso-
lated from wood chips of Picea abies and Pinus
sylvestris in Sweden, as well as from the air and
seeds of Piper nigrum in Spain [13]. Although the
precise environmental source is still unknown,
patients are thought to acquire the R. argillacea
species complex through inhalation. An envi-
ronmental study of the homes of patients with
inherited disorders associated with R. argillacea
infections (CF or CGD) should be conducted to
identify the reservoirs of the fungus and to pro-
pose prophylactic measures aiming at reducing
the exposure of the patients and preventing their
contamination. Similar studies dealing with S.
apiospermum in the CF context have led to the
identification of potted plants in the homes of
the patients as a possible cause of contamination
[Bouchara J‑P, Unpublished Data]. Development of
specific methods, such as selective or semi-selec-
tive culture media or PCR-based techniques, is
a preliminary step for such an epidemiological
study.
Moreover, considering the hypocrealan Geo-
smithia species, a close association with bark
beetles is well documented [4–6,77,78]. The dry-
spored fungi occur in galleries built by many
phloephagous bark beetles. A similar association
between collembola, which also belongs to the
Arthropoda order, and Geosmithia namyslowskii
(belonging to the eurotialean Geosmithia spe-
cies) was suggested in a study that examined
the fungal biota in Lascaux cave in France
[79]. The potential association of species of the
R. argillacea complex with Arthropoda should
be investigated.

Executive summary
Taxonomy & identification
„„The genus Rasamsonia resulted from the recent taxonomic revision of the Geosmithia genus.

„„Currently, the genus Rasamsonia comprises nine species: R. brevistipitata, R. byssochlamydoides, R. composticola, R. cyclindrospora,

R. emersonii, R. argillacea, R. eburnea, R. aegroticola and R. piperina, the four last species forming the R. argillacea species complex.
„„Species of the Rasamsonia genus are thermotolerant and are frequently misidentified as Penicillium or Paecilomyces species.

Pathogenesis
„„An increased isolation of species of the R. argillacea complex in a clinical context has been observed since 2005.

„„The pulmonary involvement reported in almost all cases suggests the respiratory tract as the main portal of entry.

„„The most frequent underlying conditions were cystic fibrosis (CF; 70% of the cases) and chronic granulomatous disease (11%).

„„The four species of the R. argillacea complex have been reported in a clinical context.

„„In vitro, all species of the R. argillacea complex are resistant to voriconazole and susceptible to echinocandins.

Clinical relevance
„„The main clinical presentation in chronic granulomatous disease patients is pneumonia. Pulmonary infiltrations frequently extend in a

contiguous manner from lungs to adjacent bones.

„„All but one species of the R. argillacea complex (R. eburnea) have been reported as being capable of chronically colonizing the CF lung.

„„In one CF patient, R. argillacea was considered to be the likely cause of recurrent asthma-like symptoms.

„„Further analysis is necessary to evaluate a potential association between airway colonization by species of the R. argillacea complex and

the CFTR genotype F508del.

Research challenges & future perspective
„„The involvement of global warming in the increased occurrence of the R. argillacea species complex remains to be investigated.

„„Development of specific detection and direct identification methods is required to clarify the ecology of these fungi and to specify the

origin of contamination of the patients.

„„An association between some arthropods and Rasamsonia species should be investigated.

future science group www.futuremedicine.com 975

 Review Giraud, Favennec, Bougnoux & Bouchara
Financial & competing interests
disclosure
The authors have no relevant affiliations or
financial involvement with any organization or
entity with a financial interest in or financial
conflict with the subject matter or materials dis-
cussed in the manuscript. This includes employ-
ment, consultancies, honoraria, stock ownership
or options, expert testimony, grants or patents
received or pending, or royalties.
No writing assistance was utilized in the
production of this manuscript.
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Papers of special note have been highlighted as:
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