Diagnostic and Interventional Imaging (2015) 96, 435—442
REVIEW /Thoracic imaging
Pulmonary aspergillosis
M.L. Chabia,∗, A. Goraccib, N. Rochec, A. Paugamd,A. Lupoe, 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, Franceb Département d’imagerie médicale, service de radiologie, IRCCS Istituto Clinico Humanitas,Via Manzoni 56, 20089 Rozzano, Italyc Service de pneumologie, hôpital d’instruction des armées du Val-de-Grâce, 74, boulevard dePort-Royal, 75230 Paris cedex 05, Franced Service de parasitologie-mycologie-médecine tropicale, hôpital Cochin, 27, rue duFaubourg-Saint-Jacques, 75679 Paris cedex 14, Francee Service d’anatomie et de cytologie pathologiques, hôpital Cochin, 27, rue duFaubourg-Saint-Jacques, 75679 Paris cedex 14, Francef Service de radiologie A, hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75679 Pariscedex 14, France
Abstract Aspergillosis is a mycotic disease usually caused by Aspergillus fumigatus, a sapro-phytic and ubiquitous airborne fungus. Aspergillus-related lung diseases are traditionallyclassified into four different forms, whose occurrence depends on the immunologic status of thehost and the existence of an underlying lung disease. Allergic broncho-pulmonary aspergillo-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-invasiveform) is described in patients with chronic lung pathology or mild immunodeficiency. Invasiveaspergillosis (angio-invasive or broncho-invasive forms) occurs in severely immuno-compromisedpatients. 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 recognitionand accurate diagnosis.
Aspergillosis is a mycotic disease caused by Aspergillus, filamentous fungus. The most common pathogenic speciesesponsible for pulmonary disease is Aspergillus fumigatus1].
A. fumigatus is a saprophytic and ubiquitous airborne fun-us, whose natural ecological niche is the soil [1]. Heat,oisture and organic matters (carpet, autumn leaves. . .)romote its development.
Humans constantly inhale numerous conidia (spores) ofhis fungus, which are normally eliminated by muco-ciliarylearance and innate immune mechanisms in immunocom-etent hosts without underlying lung disease [1].
The development of pulmonary aspergillosis requiresost’s predisposing factors such as allergic status (asthma),irways diseases (bronchial dilatation, cystic fibrosis),hronic lung cavities (tuberculosis, sarcoidosis. . .) ormmune deficiency.
Allergic reaction to Aspergillus antigens exposes tollergic broncho-pulmonary aspergillosis (ABPA). Alter-tion of muco-ciliary cells in bronchial dilatation orystic fibrosis allows colonization of the airways byspergillus. The absence of macrophages in tuberculo-is cavity and other chronic lung cavities promotes theevelopment of a ‘‘fungal ball’’ (aspergilloma). Immuno-uppression due to steroids, transplantation, or aplasiaay be responsible for chronic necrotizing forms or
nvasive forms depending on the level of immune defi-iency.
Clinical, radiological and histological manifestations ofulmonary aspergillosis depend, besides the number andirulence of the spores, mainly on the immune sta-us of the host and the presence of pre-existing lungisease.
The purpose of this review is to illustrate the radiologi-al appearance of the four categories of Aspergillus-relatedung diseases and to point out, for each, the specific immunetatus of the host.
spergillus fumigatus
. fumigatus is a saprophytic and ubiquitous airborne fila-entous fungus, whose natural ecological niche is the soil
1]. Its development is favoured by some contexts suchs heat, moisture and organic matters (carpet, autumneaves. . .).
The conidia released into the atmosphere have a diam-ter small enough (2 to 3 �m) to reach the lung alveoli1].
The concentration of spores in the air increases withonstruction or renovation of buildings (levelling, paintingepair. . .) and must be monitored if it takes place in hospi-als. Any increase in the concentration of airborne conidiaaises the risk of contracting aspergillosis in susceptible indi-iduals [1]. Mycology laboratories and haematology servicesre equipped with hoods and laminar flow to avoid aerial
ontamination.
There are other sources of contamination, less known,uch as spices (pepper) [2] and marijuana [3], which contain
lot of fumigatus spores.
cg
M.L. Chabi et al.
arious presentations of pulmonaryspergillosis
llergic broncho-pulmonary aspergillosisABPA)
BPA is an immunological pulmonary disorder caused byypersensitivity to Aspergillus fumigatus [4,5].
It nearly always affects asthmatics (1—2% of asthmaatients) or patients with cystic fibrosis (CF; 1—15% of CFatients) [6,7].
The allergic reaction to Aspergillus antigens is respon-ible for a local inflammatory reaction (with infiltrate ofosinophils, excessive mucus production and bronchial wallamage) and an airways’ filling by mucus plugs, containingspergillus and eosinophils. The result is a bronchial dilata-ion typically involving segmental and subsegmental bronchi8], with predominance in the upper lung.
Clinical manifestations include poorly controlled asthma,heezing, haemoptysis and productive cough with expec-
oration of brownish black mucus plugs. However, someatients can remain asymptomatic [4,5].
CT typically demonstrates the presence of centralronchiectasis, usually involving segmental or subsegmentalronchi, with upper lobe predominance. These bronchiec-asis are filled by mucoid impactions with an inversed Yr V shape and are also called finger-in-glove opacities [8]Fig. 1).
High attenuation or calcification of impacted mucus cane seen. High attenuation mucus, characterized by higherensity than that of paraspinal muscles, is a pathognomonicnding of ABPA [5]. Hyperattenuating mucus plugging isxplained by the presence of calcium salts and even metalsthe ions of iron and manganese) or desiccated mucus, suchs for Aspergillus sinusitis.
Occasionally, lobar or segmental atelectasis may occur.arely, pleural effusion or spontaneous pneumothorax haveeen described.
If untreated, this disease can evolve to pulmonary fibro-is.
New diagnostic criteria have been recently proposed tomprove the accuracy of ABPA diagnosis [5]. These criterianclude predisposing conditions (bronchial asthma or cysticbrosis) associated with both obligatory criteria and at leastwo of three other criteria.
Obligatory criteria are type I Aspergillus skin test posi-ivity (immediate cutaneous hypersensitivity to Aspergillusntigen) or elevated levels of specific IgE against Aspergillusumigatus and elevated total IgE levels (>1000 IU/mL). Thether three criteria are presence of precipitating or IgGntibodies against A. fumigatus in serum, radiographic pul-onary opacities consistent with ABPA and total eosinophil
ount >500 cells/L in steroid naive patients.The chest radiographic features consistent with ABPA
ay be transient (i.e. consolidation, nodules, tram-trackpacities, toothpaste/finger-in-glove opacities, fleetingpacities) or permanent (i.e. parallel line and ring shadows,ronchiectasis and pleuropulmonary fibrosis).
High-resolution computed tomography (HRCT) of thehest detects abnormalities not apparent on chest radio-raph, 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.
); e: coronal CT image after treatment. Mucus plugging has disappeared
Fl
On mediastinal windowing (d), mucus plugs are hyperdense (102 HUwhereas bronchectasis persist (head arrow).
distribution of bronchiectasis, HRCT is therefore the bestimaging modality for evaluating patients with suspectedABPA [5].
Saprophytic aspergillosis infection(aspergilloma)
Saprophytic aspergillosis infection is due to Aspergillus col-onization of a pre-existing pulmonary cavity or ectaticbronchus. It combines conglomerate of fungal hyphae,inflammatory cells, mucus and cellular debris, without anytissue 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 pulmonarycavities, emphysematous bullae, honeycomb cysts. . .).
Aspergilloma is characterized by the presence of a roundor 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 withchanges in position [8,9]. The degree of filling of the lungcavity is variable, responsible for very solid forms (pseudo-tumoral) and very cavitary forms. The key element is theidentification of the ‘‘air crescent’’ sign, for which CTscan is more effective than conventional chest radiography
(Figs. 3 and 4).
The lack of ‘‘fungus ball’’ into a cavity does not excludeaspergillosis infection, which can be characterized initiallyby an isolated wall thickening. All chronic lung cavities
c(
d
igure 2. Aspergilloma. Image of pathologic specimen afterobectomy showing a ‘‘fungus ball’’ within a cavity.
an be colonized by Aspergillus and develop aspergillomaFig. 5).
Saprophytic aspergillosis may be discovered either inci-entally 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, whichis 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 pulmonarycavity in the left lower lung apex, which is pathognomonic for aspergilloma. Chest X ray only demonstrates bilateral opacities with retractionof 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 latershows thickening of the cavity walls; c: two years later, a fungus ball with ‘‘air crescent’’ sign is demonstrated. All chronic lung cavities canb of t
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e colonized by Aspergillus and develop aspergilloma. The first sign
he main complication. Aspergillomas remain stable in theajority of cases, but can also decrease in size or even spon-
aneously resolve in about 10% of cases. Aspergillomas morearely show size increase [10].
Other causes of ‘‘air crescent’’ sign include angio-nvasive and chronic necrotizing aspergillosis. In these cases,here are no pre-existing cavities; radiological manifesta-ions appear within a few days in the angio-invasive forms
nd within several weeks or months in the chronic necrotiz-ng forms [11] (Fig. 6).
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he saprophytic infection is usually a thickening of the cavity walls.
hronic necrotizing aspergillosis (CNA) is a rare andoorly understood form of aspergillosis, which canimic other chronic pulmonary infections (tuberculosis,
istoplasmosis. . .). Its recognition and diagnosis are often
elayed.
CNA is a locally invasive disease that occurs in patientsith 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 necrotizingaspergillosis; b) and in invasive aspergillosis (c). In the latter two cases (b and c), there was not any pre-existing lung cavity; the focal areaof necrosis is due to fungal invasion.
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Radiologically, CNA is characterized by pulmonaryconsolidations, usually involving the upper lobes, withbronchiectasis. The consolidation progresses with time tocavitation over weeks to months [12,13].
As indicated earlier, a ‘‘fungal ball’’ with ‘‘air crescentsign’’ may develop in CNA as a secondary phenomenon dueto the parenchymal destruction by the fungus [11] (Fig. 7).
In 2003, Denning et al. proposed diagnostic criteria forCNA [14] (Boxed text).
Boxed text: Denning’s criteria [14] for chronicnecrotizing aspergillosis.• Chronic pulmonary or systemic symptoms (duration
3 months) compatible with CPA, including at least 1of the following symptoms: weight loss, productivecough, or haemoptysis.
• Cavitary pulmonary lesion with evidence ofparacavitary infiltrates, new cavity formation,or expansion of cavity size over time.
• Either positive result of serum Aspergillus precipitinstest or isolation of Aspergillus spp. from pulmonaryor pleural cavity.
• Elevated levels of inflammatory markers (C-reactive protein, plasma viscosity, or erythrocytesedimentation rate).
• Exclusion of other pulmonary pathogens, by resultsof appropriate cultures and serological tests, thatare associated with similar disease presentation,including mycobacteria and endemic fungi(especially Coccidioides immitis and Histoplasmacapsulatum).
• No overt immunocompromising conditions (e.g.,
HIV infection, leukemia, and chronic granulomatousdisease).
ten
nvasive aspergillosis: angio-invasive andirway-invasive forms
nvasive pulmonary aspergillosis is an aggressive disease dueo the invasion of the bronchial wall and the accompany-ng arterioles by the hyphae. This form primarily occurs ineverely immuno-compromised patients, especially patientsith neutropenia due to allogenic bone marrow transplan-
ation or chemotherapy for acute leukemia [15], but alsoatients who received solid-organ transplantation, espe-ially lung transplantation [16].
The most important risk factor is neutropenia. The risk ofnvasive aspergillosis is strongly correlated with the durationnd degree of neutropenia [11].
Symptoms are non-specific and usually mimic bron-hopneumonia, but also include pleuritic chest pain andaemoptysis [11].
Invasive aspergillosis is a diagnostic and therapeutic chal-enge due to the high morbidity and mortality.
There are two sub-categories of invasive aspergillosis,he airway-invasive form and the angio-invasive form.
The airway-invasive form accounts for 15 to 30% ofnvasive aspergillosis, and is defined by the presence ofspergillus deep to the basal membrane of the bronchi [17].
Radiologically, it can mimic bronchiolitis with patchy cen-rilobular nodules with tree-in-bud appearance, similar tohose seen in endobronchial spread of tuberculosis. A bron-hopneumonia presentation is common, with confluence oferibronchial consolidations, similar to bacterial bronchop-eumonia [8,17] (Fig. 8).
In rare cases, the fungal infection is entirely or pre-ominantly confined to the tracheobronchial tree. Acutespergillus tracheobronchitis usually occurs in lung trans-lantation recipients [16]. Radiologically, it may appear asracheal or bronchial irregular wall thickening, with occa-ionally high attenuation aspect due to ability of Aspergillus
o fix calcium. Atelectasis or endobronchial masses haveven been described. However, most of the time, there areo 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 andd: correspond to CT images of the same patient 5 months (c) and 7 months (d) latter. Progressive cavitation of the initial consolidation isseen; e and f: are chest radiographs corresponding to CT scans images c and d. They show a progressive cavitation of the right upper lobe.C t thes
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omparison with the first available chest X ray is crucial, to detecource of delayed diagnosis.
The angio-invasive form is histologically characterizedy the invasion and occlusion of small to medium-sizeulmonary arteries by fungal hyphae [8]. Typical CT find-ngs [8,17] consist in larges nodules surrounded by groundlass attenuation, which is called the ‘‘halo sign’’. Nod-
les are due to coagulation necrosis, whereas the halof ground glass is due to surrounding alveolar haemorr-age [19] (Fig. 9). Other findings are pleura-based areas of
Hus
igure 8. Broncho-invasive aspergillosis in a 50-year-old man with alloilateral lobular consolidation with centrilobular nodules in the left lowould also be due to bacterial bronchopneumonia.
progressive cavitation because changes occur slowly, which is the
onsolidation, similar to those seen in pulmonary infarctsomplicating pulmonary embolism, correspond to haemor-hagic infarcts.
Differential diagnoses of ‘‘halo sign’’ in neu-ropenic patients include infections due to Candida,
erpes simplex and cytomegalovirus, Wegener gran-lomatosis, haemorrhagic metastases and Kaposiarcoma.
genic bone marrow transplantation. Axial CT images (a, b) showinger lobe (b). These features are non-specific of fungal infection and
Pulmonary aspergillosis
Figure 9. Angio-invasive aspergillosis in a 31-year-old-womanwith lung transplantation. Axial CT image showing a large nod-
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ule in the right lower lobe surrounded by a halo of ground glassattenuation (halo sign).
The occurrence of cavitation within a nodule or aconsolidation is often concomitant with the resolution ofneutropenia. In this late phase, the separation of thenecrotic lung fragment from the adjacent lung parenchymaresults in an ‘‘air crescent’’ sign similar to that observed inaspergilloma. Unlike saprophytic aspergillosis infection, theopacity surrounded by a crescent airspace develops in lessthan 2 weeks and without pre-existing cavity (Fig. 10).
Therefore, it is essential to think in terms of immunolog-ical status and fastness of evolution in case of cavitation.
There are increasing numbers of reports documentinginvasive aspergillosis in immunocompetent patients withsevere COPD, often with prolonged use of corticosteroidtherapy [11].
Overlap between these various manifestations
Beyond this segmentation in four forms it should be notedthat an overlap between the main categories of Aspergillus-related diseases has been reported. Some forms couldco-exist, especially allergic broncho-pulmonary aspergillosisand aspergilloma [11,20].
Changes of local or systemic host immunity and of under-lying lung pathology can modify aspergillosis pulmonarymanifestations with time. For example, an aspergilloma candevelop within bronchiectasis in a patient with ABPA. An
B
Ba
Figure 10. a: axial CT image in a leukemia patient showing a right uppc: axial and coronal CT images acquired 3 weeks later showing an ‘‘air craspergilloma but is relevant to a necrotic lung fragment in an angio-inva
441
nvasive form can complicate long-standing ABPA in case ofystemic immune deficiency, including the use of high-dosef steroids [20].
ycological diagnosis: which samplellows diagnosis?
putum
irect examination can be made to identify the presence oflaments.
The significance of isolating Aspergillus in sputum sam-les depends on the immune status of the host. Inmmunocompetent patients, it represents at least a colo-ization, while it is highly predictive of invasive diseasen immuno-compromised patients [11]. Conversely, negativeputum samples do not rule out aspergillosis, including inva-ive forms [11]. The results of cultures are often delayed.
erum
etection of IgG antibodies against A. fumigatus in theerum helps the diagnosis of aspergilloma or ABPA, the twoorms of aspergillosis observed in immunocompetent indi-iduals [1]. It can be negative in patients on corticosteroidherapy.
In contrast to immunocompetent hosts, growth of. fumigatus in the tissues of an immunosuppressed host isot correlated with an increase in anti-Aspergillus antibodyiters [1]. Consequently, detection of Aspergillus antigens inhe serum is more useful for diagnosing invasive aspergillosisn immuno-compromised patients (ELISA, latex agglutina-ion). Galactomannan is the most commonly used antigen,t is a polysaccharide fungal cell wall component releaseduring hyphal growth in tissues. It is reported that serumalactomannan can be detected several days before theresence of clinical symptoms, chest radiographic abnor-alities or positive culture [11].Another possibility is the detection of A. fumigatus DNA
y PCR.
ronchoalveolar lavage (BAL)
AL is useful to identify Aspergillus by direct examinationnd culture.
er lobe nodule surrounded by mild ground glass attenuation; b andescent’’ sign surrounding a focal opacity. This feature is similar tosive form of aspergillosis.
Further, as for serum, Aspergillus antigens (galactoman-an) and A. fumigatus DNA (by PCR) can be detected in BAL21].
iopsy
he histopathological examination of lung tissue with posi-ive culture is the gold standard for the diagnosis of invasivespergillosis [11]. Nevertheless, surgical biopsies are infre-uently performed, only for diagnosis purposes in fragileatients.
onclusion
he spectrum of respiratory diseases caused by Aspergilluss wide. It includes hypersensitivity in ABPA, saprophyticnfection in pre-existing broncho-pulmonary diseases andemi-invasive or invasive forms in immuno-compromisedatients.
The correlation between the immunologic status of theost, an essential factor in the occurrence of Aspergillus-elated lung diseases, and the radiological presentation is ofajor importance for accurate diagnosis of these diseases.
isclosure of interest
he authors declare that they have no conflicts of interestoncerning this article.
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