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Diagnostic and Interventional Imaging (2015) 96, 435—442

REVIEW /Thoracic imaging

Pulmonary aspergillosis
M.L. Chabi a,∗, A. Goracci b, N. Roche c, A. Paugam d,
A. Lupo e, M.P. Revel f

a
Service de radiologie polyvalente et oncologique, groupe hospitalier de la Pitié-Salpêtrière
— Charles-Foix, AP—HP, 83, boulevard de l’Hôpital, 75651 Paris cedex 13, France
b
Département d’imagerie médicale, service de radiologie, IRCCS Istituto Clinico Humanitas,
Via Manzoni 56, 20089 Rozzano, Italy
c
Service de pneumologie, hôpital d’instruction des armées du Val-de-Grâce, 74, boulevard de
Port-Royal, 75230 Paris cedex 05, France
d
Service de parasitologie-mycologie-médecine tropicale, hôpital Cochin, 27, rue du
Faubourg-Saint-Jacques, 75679 Paris cedex 14, France
e
Service d’anatomie et de cytologie pathologiques, hôpital Cochin, 27, rue du
Faubourg-Saint-Jacques, 75679 Paris cedex 14, France
f
Service de radiologie A, hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75679 Paris
cedex 14, France

KEYWORDS Abstract Aspergillosis is a mycotic disease usually caused by Aspergillus fumigatus, a sapro-
Aspergillosis; phytic and ubiquitous airborne fungus. Aspergillus-related lung diseases are traditionally
Lung infections; classified into four different forms, whose occurrence depends on the immunologic status of the
Computed host and the existence of an underlying lung disease. Allergic broncho-pulmonary aspergillo-
tomography sis (ABPA) affects patients with asthma or cystic fibrosis. Saprophytic infection (aspergilloma)
occurs in patients with abnormal airways (chronic obstructive pulmonary disease, bronchiec-
tasis, cystic fibrosis) or chronic lung cavities. Chronic necrotizing aspergillosis (semi-invasive
form) is described in patients with chronic lung pathology or mild immunodeficiency. Invasive
aspergillosis (angio-invasive or broncho-invasive forms) occurs in severely immuno-compromised
patients. Knowledge of the various radiological patterns for each form, as well as the corre-
sponding associated immune disorders and/or underlying lung diseases, helps early recognition
and accurate diagnosis.
© 2015 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Abbreviations: A. fumigatus, Aspergillus fumigatus; ABPA, allergic broncho-pulmonary aspergillosis; COPD, chronic obstructive pul-
monary disease; CF, cystic fibrosis; HRCT, high-resolution computed tomography; CAN, chronic necrotizing aspergillosis; BAL, bronchoalveolar
lavage.
∗ Corresponding author.

E-mail address: marie-laure.chabi@psl.aphp.fr (M.L. Chabi).


http://dx.doi.org/10.1016/j.diii.2015.01.005
2211-5684/© 2015 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.
436 M.L. Chabi et al.

Aspergillosis is a mycotic disease caused by Aspergillus, Various presentations of pulmonary


a filamentous fungus. The most common pathogenic species
responsible for pulmonary disease is Aspergillus fumigatus
aspergillosis
[1]. Allergic broncho-pulmonary aspergillosis
A. fumigatus is a saprophytic and ubiquitous airborne fun-
gus, whose natural ecological niche is the soil [1]. Heat,
(ABPA)
moisture and organic matters (carpet, autumn leaves. . .)
ABPA is an immunological pulmonary disorder caused by
promote its development.
hypersensitivity to Aspergillus fumigatus [4,5].
Humans constantly inhale numerous conidia (spores) of
It nearly always affects asthmatics (1—2% of asthma
this fungus, which are normally eliminated by muco-ciliary
patients) or patients with cystic fibrosis (CF; 1—15% of CF
clearance and innate immune mechanisms in immunocom-
patients) [6,7].
petent hosts without underlying lung disease [1].
The allergic reaction to Aspergillus antigens is respon-
The development of pulmonary aspergillosis requires
sible for a local inflammatory reaction (with infiltrate of
host’s predisposing factors such as allergic status (asthma),
eosinophils, excessive mucus production and bronchial wall
airways diseases (bronchial dilatation, cystic fibrosis),
damage) and an airways’ filling by mucus plugs, containing
chronic lung cavities (tuberculosis, sarcoidosis. . .) or
Aspergillus and eosinophils. The result is a bronchial dilata-
immune deficiency.
tion typically involving segmental and subsegmental bronchi
Allergic reaction to Aspergillus antigens exposes to
[8], with predominance in the upper lung.
allergic broncho-pulmonary aspergillosis (ABPA). Alter-
Clinical manifestations include poorly controlled asthma,
ation of muco-ciliary cells in bronchial dilatation or
wheezing, haemoptysis and productive cough with expec-
cystic fibrosis allows colonization of the airways by
toration of brownish black mucus plugs. However, some
Aspergillus. The absence of macrophages in tuberculo-
patients can remain asymptomatic [4,5].
sis cavity and other chronic lung cavities promotes the
CT typically demonstrates the presence of central
development of a ‘‘fungal ball’’ (aspergilloma). Immuno-
bronchiectasis, usually involving segmental or subsegmental
suppression due to steroids, transplantation, or aplasia
bronchi, with upper lobe predominance. These bronchiec-
may be responsible for chronic necrotizing forms or
tasis are filled by mucoid impactions with an inversed Y
invasive forms depending on the level of immune defi-
or V shape and are also called finger-in-glove opacities [8]
ciency.
(Fig. 1).
Clinical, radiological and histological manifestations of
High attenuation or calcification of impacted mucus can
pulmonary aspergillosis depend, besides the number and
be seen. High attenuation mucus, characterized by higher
virulence of the spores, mainly on the immune sta-
density than that of paraspinal muscles, is a pathognomonic
tus of the host and the presence of pre-existing lung
finding of ABPA [5]. Hyperattenuating mucus plugging is
disease.
explained by the presence of calcium salts and even metals
The purpose of this review is to illustrate the radiologi-
(the ions of iron and manganese) or desiccated mucus, such
cal appearance of the four categories of Aspergillus-related
as for Aspergillus sinusitis.
lung diseases and to point out, for each, the specific immune
Occasionally, lobar or segmental atelectasis may occur.
status of the host.
Rarely, pleural effusion or spontaneous pneumothorax have
been described.
If untreated, this disease can evolve to pulmonary fibro-
sis.
New diagnostic criteria have been recently proposed to
Aspergillus fumigatus improve the accuracy of ABPA diagnosis [5]. These criteria
A. fumigatus is a saprophytic and ubiquitous airborne fila- include predisposing conditions (bronchial asthma or cystic
mentous fungus, whose natural ecological niche is the soil fibrosis) associated with both obligatory criteria and at least
[1]. Its development is favoured by some contexts such two of three other criteria.
as heat, moisture and organic matters (carpet, autumn Obligatory criteria are type I Aspergillus skin test posi-
leaves. . .). tivity (immediate cutaneous hypersensitivity to Aspergillus
The conidia released into the atmosphere have a diam- antigen) or elevated levels of specific IgE against Aspergillus
eter small enough (2 to 3 ␮m) to reach the lung alveoli fumigatus and elevated total IgE levels (>1000 IU/mL). The
[1]. other three criteria are presence of precipitating or IgG
The concentration of spores in the air increases with antibodies against A. fumigatus in serum, radiographic pul-
construction or renovation of buildings (levelling, painting monary opacities consistent with ABPA and total eosinophil
repair. . .) and must be monitored if it takes place in hospi- count >500 cells/L in steroid naive patients.
tals. Any increase in the concentration of airborne conidia The chest radiographic features consistent with ABPA
raises the risk of contracting aspergillosis in susceptible indi- may be transient (i.e. consolidation, nodules, tram-track
viduals [1]. Mycology laboratories and haematology services opacities, toothpaste/finger-in-glove opacities, fleeting
are equipped with hoods and laminar flow to avoid aerial opacities) or permanent (i.e. parallel line and ring shadows,
contamination. bronchiectasis and pleuropulmonary fibrosis).
There are other sources of contamination, less known, High-resolution computed tomography (HRCT) of the
such as spices (pepper) [2] and marijuana [3], which contain chest detects abnormalities not apparent on chest radio-
a lot of fumigatus spores. graph, and allows better assessment of the pattern and
Pulmonary aspergillosis 437

Figure 1. A 30-year-old asthmatic man with productive cough and dyspnea. Axial (a) and coronal (b, c) CT images show bilateral subseg-
mental bronchectasis filled with mucus (arrows). These images are called finger-in-glove opacities and are consistent with ABPA diagnosis.
On mediastinal windowing (d), mucus plugs are hyperdense (102 HU); e: coronal CT image after treatment. Mucus plugging has disappeared
whereas bronchectasis persist (head arrow).

distribution of bronchiectasis, HRCT is therefore the best


imaging modality for evaluating patients with suspected
ABPA [5].

Saprophytic aspergillosis infection


(aspergilloma)
Saprophytic aspergillosis infection is due to Aspergillus col-
onization of a pre-existing pulmonary cavity or ectatic
bronchus. It combines conglomerate of fungal hyphae,
inflammatory cells, mucus and cellular debris, without any
tissue invasion (Fig. 2).
This infection occurs in patients with abnormal airways
(COPD, bronchiectasis, cystic fibrosis) or chronic lung cavi-
ties such as tuberculous caverns, sarcoid-related pulmonary
cavities, emphysematous bullae, honeycomb cysts. . .).
Aspergilloma is characterized by the presence of a round
or oval mass within a pulmonary cavity, typically sur-
rounded by an airspace, resulting in the ‘‘air crescent’’
sign (Figs. 3 and 4). The ‘‘fungus ball’’ usually moves with
changes in position [8,9]. The degree of filling of the lung
cavity is variable, responsible for very solid forms (pseudo-
tumoral) and very cavitary forms. The key element is the Figure 2. Aspergilloma. Image of pathologic specimen after
identification of the ‘‘air crescent’’ sign, for which CT lobectomy showing a ‘‘fungus ball’’ within a cavity.
scan is more effective than conventional chest radiography
(Figs. 3 and 4). can be colonized by Aspergillus and develop aspergilloma
The lack of ‘‘fungus ball’’ into a cavity does not exclude (Fig. 5).
aspergillosis infection, which can be characterized initially Saprophytic aspergillosis may be discovered either inci-
by an isolated wall thickening. All chronic lung cavities dentally or after an episode of haemoptysis, which is
438 M.L. Chabi et al.

Figure 3. Coronal (a) and sagittal (b) CT images showing pathognomonic aspergilloma: mass within a lung cavity surrounded by air, which
is called the ‘‘air crescent’’ sign. Aspergilloma cannot be diagnosed on chest X ray (c), because the air crescent sign is not visible.

Figure 4. a: tuberculosis sequelae in pulmonary apices on chest X ray; b and c: CT images demonstrate a fungus ball within a pulmonary
cavity in the left lower lung apex, which is pathognomonic for aspergilloma. Chest X ray only demonstrates bilateral opacities with retraction
of both lung apices.

Figure 5. a: axial CT image showing a broncho-pleural fistula complicating left upper lobe resection; b: CT scan performed 1 year later
shows thickening of the cavity walls; c: two years later, a fungus ball with ‘‘air crescent’’ sign is demonstrated. All chronic lung cavities can
be colonized by Aspergillus and develop aspergilloma. The first sign of the saprophytic infection is usually a thickening of the cavity walls.

the main complication. Aspergillomas remain stable in the Chronic necrotizing aspergillosis (former
majority of cases, but can also decrease in size or even spon- semi-invasive form)
taneously resolve in about 10% of cases. Aspergillomas more
rarely show size increase [10]. Chronic necrotizing aspergillosis (CNA) is a rare and
Other causes of ‘‘air crescent’’ sign include angio- poorly understood form of aspergillosis, which can
invasive and chronic necrotizing aspergillosis. In these cases, mimic other chronic pulmonary infections (tuberculosis,
there are no pre-existing cavities; radiological manifesta- histoplasmosis. . .). Its recognition and diagnosis are often
tions appear within a few days in the angio-invasive forms delayed.
and within several weeks or months in the chronic necrotiz- CNA is a locally invasive disease that occurs in patients
ing forms [11] (Fig. 6). with chronic lung pathology [12] or mild immunodeficiency
Pulmonary aspergillosis 439

Figure 6. ‘‘Air crescent’’ sign. Axial CT images of 3 different patients, showing a lung parenchyma opacity surrounded by an ‘‘air crescent’’
sign. This feature is not specific of saprophytic infection (aspergilloma; a), it can be seen in semi-invasive aspergillosis (chronic necrotizing
aspergillosis; b) and in invasive aspergillosis (c). In the latter two cases (b and c), there was not any pre-existing lung cavity; the focal area
of necrosis is due to fungal invasion.

such as long-standing steroid therapy, diabetes, renal fail- Invasive aspergillosis: angio-invasive and
ure, COPD. . . airway-invasive forms
Radiologically, CNA is characterized by pulmonary
consolidations, usually involving the upper lobes, with Invasive pulmonary aspergillosis is an aggressive disease due
bronchiectasis. The consolidation progresses with time to to the invasion of the bronchial wall and the accompany-
cavitation over weeks to months [12,13]. ing arterioles by the hyphae. This form primarily occurs in
As indicated earlier, a ‘‘fungal ball’’ with ‘‘air crescent severely immuno-compromised patients, especially patients
sign’’ may develop in CNA as a secondary phenomenon due with neutropenia due to allogenic bone marrow transplan-
to the parenchymal destruction by the fungus [11] (Fig. 7). tation or chemotherapy for acute leukemia [15], but also
In 2003, Denning et al. proposed diagnostic criteria for patients who received solid-organ transplantation, espe-
CNA [14] (Boxed text). cially lung transplantation [16].
The most important risk factor is neutropenia. The risk of
invasive aspergillosis is strongly correlated with the duration
and degree of neutropenia [11].
Symptoms are non-specific and usually mimic bron-
Boxed text: Denning’s criteria [14] for chronic
chopneumonia, but also include pleuritic chest pain and
necrotizing aspergillosis.
• Chronic pulmonary or systemic symptoms (duration haemoptysis [11].
Invasive aspergillosis is a diagnostic and therapeutic chal-
3 months) compatible with CPA, including at least 1
lenge due to the high morbidity and mortality.
of the following symptoms: weight loss, productive
There are two sub-categories of invasive aspergillosis,
cough, or haemoptysis.
• Cavitary pulmonary lesion with evidence of the airway-invasive form and the angio-invasive form.
The airway-invasive form accounts for 15 to 30% of
paracavitary infiltrates, new cavity formation,
invasive aspergillosis, and is defined by the presence of
or expansion of cavity size over time.
• Either positive result of serum Aspergillus precipitins Aspergillus deep to the basal membrane of the bronchi [17].
Radiologically, it can mimic bronchiolitis with patchy cen-
test or isolation of Aspergillus spp. from pulmonary
trilobular nodules with tree-in-bud appearance, similar to
or pleural cavity.
• Elevated levels of inflammatory markers (C- those seen in endobronchial spread of tuberculosis. A bron-
chopneumonia presentation is common, with confluence of
reactive protein, plasma viscosity, or erythrocyte
peribronchial consolidations, similar to bacterial bronchop-
sedimentation rate).
• Exclusion of other pulmonary pathogens, by results neumonia [8,17] (Fig. 8).
In rare cases, the fungal infection is entirely or pre-
of appropriate cultures and serological tests, that
dominantly confined to the tracheobronchial tree. Acute
are associated with similar disease presentation,
Aspergillus tracheobronchitis usually occurs in lung trans-
including mycobacteria and endemic fungi
plantation recipients [16]. Radiologically, it may appear as
(especially Coccidioides immitis and Histoplasma
tracheal or bronchial irregular wall thickening, with occa-
capsulatum).
• No overt immunocompromising conditions (e.g., sionally high attenuation aspect due to ability of Aspergillus
to fix calcium. Atelectasis or endobronchial masses have
HIV infection, leukemia, and chronic granulomatous
even been described. However, most of the time, there are
disease).
no detectable radiological abnormalities [8,18].
440 M.L. Chabi et al.

Figure 7. Chronic necrotizing aspergillosis; a and b: axial CT images showing a right upper lobe consolidation with bronchectasis; c and
d: correspond to CT images of the same patient 5 months (c) and 7 months (d) latter. Progressive cavitation of the initial consolidation is
seen; e and f: are chest radiographs corresponding to CT scans images c and d. They show a progressive cavitation of the right upper lobe.
Comparison with the first available chest X ray is crucial, to detect the progressive cavitation because changes occur slowly, which is the
source of delayed diagnosis.

The angio-invasive form is histologically characterized consolidation, similar to those seen in pulmonary infarcts
by the invasion and occlusion of small to medium-size complicating pulmonary embolism, correspond to haemor-
pulmonary arteries by fungal hyphae [8]. Typical CT find- rhagic infarcts.
ings [8,17] consist in larges nodules surrounded by ground Differential diagnoses of ‘‘halo sign’’ in neu-
glass attenuation, which is called the ‘‘halo sign’’. Nod- tropenic patients include infections due to Candida,
ules are due to coagulation necrosis, whereas the halo Herpes simplex and cytomegalovirus, Wegener gran-
of ground glass is due to surrounding alveolar haemorr- ulomatosis, haemorrhagic metastases and Kaposi
hage [19] (Fig. 9). Other findings are pleura-based areas of sarcoma.

Figure 8. Broncho-invasive aspergillosis in a 50-year-old man with allogenic bone marrow transplantation. Axial CT images (a, b) showing
bilateral lobular consolidation with centrilobular nodules in the left lower lobe (b). These features are non-specific of fungal infection and
could also be due to bacterial bronchopneumonia.
Pulmonary aspergillosis 441

invasive form can complicate long-standing ABPA in case of


systemic immune deficiency, including the use of high-dose
of steroids [20].

Mycological diagnosis: which sample


allows diagnosis?
Sputum
Direct examination can be made to identify the presence of
filaments.
The significance of isolating Aspergillus in sputum sam-
ples depends on the immune status of the host. In
immunocompetent patients, it represents at least a colo-
nization, while it is highly predictive of invasive disease
Figure 9. Angio-invasive aspergillosis in a 31-year-old-woman in immuno-compromised patients [11]. Conversely, negative
with lung transplantation. Axial CT image showing a large nod- sputum samples do not rule out aspergillosis, including inva-
ule in the right lower lobe surrounded by a halo of ground glass sive forms [11]. The results of cultures are often delayed.
attenuation (halo sign).

The occurrence of cavitation within a nodule or a Serum


consolidation is often concomitant with the resolution of
Detection of IgG antibodies against A. fumigatus in the
neutropenia. In this late phase, the separation of the
serum helps the diagnosis of aspergilloma or ABPA, the two
necrotic lung fragment from the adjacent lung parenchyma
forms of aspergillosis observed in immunocompetent indi-
results in an ‘‘air crescent’’ sign similar to that observed in
viduals [1]. It can be negative in patients on corticosteroid
aspergilloma. Unlike saprophytic aspergillosis infection, the
therapy.
opacity surrounded by a crescent airspace develops in less
In contrast to immunocompetent hosts, growth of
than 2 weeks and without pre-existing cavity (Fig. 10).
A. fumigatus in the tissues of an immunosuppressed host is
Therefore, it is essential to think in terms of immunolog-
not correlated with an increase in anti-Aspergillus antibody
ical status and fastness of evolution in case of cavitation.
titers [1]. Consequently, detection of Aspergillus antigens in
There are increasing numbers of reports documenting
the serum is more useful for diagnosing invasive aspergillosis
invasive aspergillosis in immunocompetent patients with
in immuno-compromised patients (ELISA, latex agglutina-
severe COPD, often with prolonged use of corticosteroid
tion). Galactomannan is the most commonly used antigen,
therapy [11].
it is a polysaccharide fungal cell wall component released
during hyphal growth in tissues. It is reported that serum
Overlap between these various manifestations galactomannan can be detected several days before the
presence of clinical symptoms, chest radiographic abnor-
Beyond this segmentation in four forms it should be noted
malities or positive culture [11].
that an overlap between the main categories of Aspergillus-
Another possibility is the detection of A. fumigatus DNA
related diseases has been reported. Some forms could
by PCR.
co-exist, especially allergic broncho-pulmonary aspergillosis
and aspergilloma [11,20].
Changes of local or systemic host immunity and of under- Bronchoalveolar lavage (BAL)
lying lung pathology can modify aspergillosis pulmonary
manifestations with time. For example, an aspergilloma can BAL is useful to identify Aspergillus by direct examination
develop within bronchiectasis in a patient with ABPA. An and culture.

Figure 10. a: axial CT image in a leukemia patient showing a right upper lobe nodule surrounded by mild ground glass attenuation; b and
c: axial and coronal CT images acquired 3 weeks later showing an ‘‘air crescent’’ sign surrounding a focal opacity. This feature is similar to
aspergilloma but is relevant to a necrotic lung fragment in an angio-invasive form of aspergillosis.
442 M.L. Chabi et al.

Further, as for serum, Aspergillus antigens (galactoman- fibrosis — state of the art: Cystic Fibrosis Foundation Consensus
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The authors declare that they have no conflicts of interest
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