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Radiology of Infectious Diseases 3 (2016) 192e200


The many faces of pulmonary aspergillosis: Imaging findings with

pathologic correlation
Prasad Panse*, Maxwell Smith1, Kristopher Cummings, Eric Jensen, Michael Gotway,
Clinton Jokerst
Department of Cardiothoracic Radiology, Mayo Clinic, Scottsdale, AZ, USA
Received 16 July 2016; revised 20 October 2016; accepted 20 October 2016
Available online 8 December 2016


Introduction: Pulmonary Aspergillus infection can manifest as a variety of forms depending on the patients underlying immune status, the load of
the organisms and the underlying condition of the lungs.
Discussion: Hypersensitivity pneumonitis and allergic bronchopulmonary Aspergillosis (ABPA) are typically seen in patients with hyper-
immune status (asthma, atopy and hyper-eosinophilia). Aspergilloma or mycetoma is seen in patients with preexisting lung damage and cav-
ities commonly from prior TB or sarcoidosis. In patients with immunosuppression, Aspergillus infection can present as semi-invasive or invasive
(angioinvasive and airway invasive) aspergillosis.
Conclusion: In this article we correlate the radiologic findings of the various pulmonary manifestations of Aspergillus infection with their
pathologic features to better understand the disease process and better comprehend the associated imaging patterns.
© 2016 Beijing You'an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (

Keywords: Pulmonary aspergillosis; Radiology; Pathology

1. Introduction [4]. These infections can be life threatening and early diag-
nosis and initiation of therapy is critical in these immuno-
Aspergillus fungus is ubiquitous and found in soil, decaying suppressed patients.
vegetation and dust. Exposure to the fungus is through the Awareness of the clinical presentation and recognition of
respiratory tract but the disease does not typically manifest the different radiological and pathological findings may help
unless it encounters weakened lungs or an impaired immune the radiologist suggest the correct diagnosis and initiate life-
system [1]. saving antifungal therapy.
The incidence of fungal infection has increased signifi-
cantly over the last few decades in part because of the 2. Discussion
increased number of hematopoietic stem cell and solid organ
transplants [2]. Aspergillosis is the most common fungal 2.1. Immune status and spectrum of disease
infection in stem cell transplant patients [3] and second most
common fungal infection in solid organ transplant recipients The probability of pulmonary aspergillosis and the radio-
logic imaging spectrum varies depending on the patients' im-
mune status as well as the condition of the lungs (Table 1).

* Corresponding author. Fax: þ1 480 301 4303. 2.2. Allergic bronchopulmonary aspergillosis
E-mail address: (P. Panse).
Peer review under responsibility of Beijing You'an Hospital affiliated to
Capital Medical University. Allergic Bronchopulmonary aspergillosis (ABPA) is a hy-
Department of Pathology, Mayo Clinic, Scottsdale, AZ, USA. persensitivity reaction to Aspergillus, most commonly A.
2352-6211/© 2016 Beijing You'an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V. This is an open access article under
the CC BY-NC-ND license (
P. Panse et al. / Radiology of Infectious Diseases 3 (2016) 192e200 193

Table 1 attenuation mucus in the setting of chronic fungal infection

Immune status and spectrum of disease. was first described in the setting of chronic fungal sinusitis and
Immunity status Lung Disease spectrum is thought to represent calcium and/or metallic ions from the
condition fungus within the inspissated mucus [11]. Differential con-
Hyperimmune Normal Hypersensitivity Pneumonitis/Allergic siderations may include bronchial atresia, tuberculosis or other
Bronchopulmonary Aspergillosis endobronchial lesions. Rarely extensive ABPA may present
Normal Preexisting Mycetoma (Aspergilloma)
with a miliary pattern on CT [12].
Immunosuppressed Normal Semi invasive Pathologic features
Invasive (Airway invasive/
Angioinvasive) A spectrum of histologic changes may be seen in the setting of
ABPA including mucoid impaction of bronchi, allergic mucin,
eosinophilic pneumonia, bronchocentric granulomatosis, and
fumigatus. Clinically patients present with wheezing, cough, acute and chronic bronchiolitis [13e16]. Mucoid impaction of
pain or low grade fever and nearly always have a prolonged bronchi or bronchioles is characterized by bronchiectasis or
history of asthma. Lab testing may reveal peripheral eosino- bronchioloectasis with mucin distention of the airway lumen
philia, elevated serum IgE levels, and skin reactivity to (Fig. 3A). The mucin may show histologic features of allergic
Aspergillus antigen [5]. The treatment usually consists of mucin including numerous eosinophils, layering of eosinophils,
steroid therapy to blunt the hypersensitivity reaction, although and Charcot-Leyden crystals (Fig. 3B and C). The fungal or-
some of the newer generation antifungal medications also ganisms may be quite rare and despite multiple GMS stains on
show promise [6,7]. separate levels, fungal elements are not identified on some cases
(Fig. 3D). The respiratory epithelium in the background may
Radiologic features show asthma-related changes, including goblet cell metaplasia,
basement membrane thickening, and eosinophilic infiltration
Plain radiographs are less sensitive early in the disease (Fig. 3C). Some cases of ABPA may have a component of
process and may only demonstrate thickening of the airways eosinophilic pneumonia (EP) (Fig. 4). EP is characterized by
and hyperinflation suggestive of asthma. More advanced dis- airspace fibrin, numerous eosinophils embedded within the
ease can demonstrate central tubular opacities in a branching fibrin, and reactive type 2 pneumocytes (Fig. 5A). Bronchocen-
pattern, more commonly in an upper lobe distribution tric granulomatosis (BG) is defined as the replacement of distal
(Fig. 1A). These findings represent central bronchiectasis with airways with necrotizing granulomas where the necrosis fills the
mucoid impaction classically described as the “finger in glove airway lumen and the epithelium is replaced by palisaded his-
sign” (arrows Fig. 1A) [8e10]. On CT, “V” or “Y” central tiocytes with or without giant cells (Fig. 5B). The key histologic
tubular opacities filled with high density are noted most feature is the recognition of the airway distribution of the gran-
compatible with dilated bronchi with mucoid impaction. These ulomas. This can be assisted with the use of elastic tissue stains.
are often associated atelectasis or hyperinflation. The bron- BG can be seen in the setting of ABPA or may be an isolated
chiectasis is central and the mucoid impaction often demon- finding of Aspergillus infection. The differential diagnosis of BG
strates a characteristic increased attenuation on CT, high includes ABPA, other infection (bacterial, fungal, parasite),
attenuation mucus or “HAM” (Figs. 1BeC, and 2AeF). High connective tissue disease (rheumatoid arthritis, granulomatosis

Fig. 1. Frontal radiograph in a patient with asthma shows central bronchiectasis and high density mucoid impactions (ABPA) in the bilateral upper lobes (finger-in-
glove sign) (1A). Computerized tomography in two patients with ABPA shows central bronchiectasis and high density mucoid impactions (ABPA) in right middle
lobe (1B, 1C).
194 P. Panse et al. / Radiology of Infectious Diseases 3 (2016) 192e200

Fig. 2. Computerized tomography in two patients with ABPA shows central bronchiectasis and high density mucoid impactions (ABPA) in left upper lobe (2A, 2B,
2C) and right middle lobe (2D, 2E, 2F).

Fig. 3. A. Extensive bronchiolectasis with marked mucoid impaction characterized by the light blue material in the lumens of the dilated airways. B. Allergic
mucin characterized by layers of eosinophil aggregates in a background of light blue mucin. C. Allergic mucin with Carcot-Leyden crystals (arrow) and eo-
sinophils. Note the asthma changes in the respiratory epithelium, including goblet cell metaplasia, intraepithelial eosinophils, and thickening of the basement
membrane. D. Rare fungal elements identified in the allergic mucin in a case of allergic bronchopulmonary aspergillosis (Grocott's methenamine silver stain).
P. Panse et al. / Radiology of Infectious Diseases 3 (2016) 192e200 195

Fig. 4. Peripheral upper lung consolidation on radiograph (A-circle) and CT (B) in 63 year old man with fever and chills. Radiographic and histopathologic (not
shown) findings were consistent with eosinophilic pneumonia.

Fig. 5. A. Eosinophilic pneumonia in a case of allergic bronchopulmonary aspergillosis characterized by fibrin in the air spaces, numerous eosinophils, and reactive
type-2 pneumocytes. B. Bronchocentric granulomatosis with necrotizing granulomas replacing the airway. Note the palisading histiocytes surrounding the central
necrotic debris.

with polyangiitis), and necrotizing sarcodidosis. Infectious stains mycetoma (Fig. 6A and B) [18]. The mass may move around
such as GMS and AFB are required. within the cavity with changes in patient position. Crescentic
lucency surrounding the peripheral aspect of the mass abutting
2.3. Aspergilloma the wall of the cavity reflects air between the fungus ball and
the wall of the cavity. This finding was originally described by
An Aspergilloma is a type of mycetoma or “fungus ball” Monod et al. [19] and was classically described as “Monod's
usually caused by a saprophytic (non-invasive) colonization by Sign” although the “air crescent sign, (arrows Fig. 6C)” a term
A. fumigatus. Aspergillomas are encountered in patients with also used to describe improving angioinvasive aspergillosis is
preexisting lung damage, most commonly cavities from prior often used interchangeably [20]. On CT, a round, heteroge-
tuberculosis or sarcoidosis (Rad Fig. 6F and G) that are neous soft tissue mass, which may contain some internal flecks
colonized by the organism. Other uncommon causes may of gas, is seen within a cavity, more commonly in the upper
include preexisting pneumatoceles, pulmonary sequestration lobes, in a dependent position with an adjacent crescent of air
or bronchogenic cyst [10]. The most common presenting and associated pleural thickening (Fig. 6DeG).
symptom in patients with an aspergilloma is hemoptysis which
can be treated with bronchial artery particle embolization or Pathologic features
surgical resection [17].
The histologic hallmark of aspergilloma or mycetoma is the
Radiologic features growth of fungal hyphae to create a mass of fungal elements
within a preexisting space, cyst, or dilated airway (Fig. 7A)
Plain radiographic findings may show pleural thickening [10]. For this reason, mycetoma is usually diagnosed on sur-
particularly in the lung apices (arrows Fig. 4). A soft tissue gical lung biopsy. The wall of the space is usually fibrotic
mass in a pre-existing cavity is characteristic finding of a with an attenuated epithelial lining. There is often a mild
196 P. Panse et al. / Radiology of Infectious Diseases 3 (2016) 192e200

Fig. 6. A, B: Preexisting cavity (arrows) on the frontal radiograph (A). Follow up radiograph (B) shows interval development of fungal ball in the cavity
(aspergilloma). Pleural thickening in the left apex also noted. C, D Axial CT image shows a mycetoma (C) with air-crescent sign {arrows} in preexisting cavity (D).
Coronal reconstruction (E) in a patient with aspergilloma shows fungal ball in a cavity with associated air crescent sign and extensive pleural thickening in the left
lung apex. Axial images (F, G) displayed in lung windows in a patient with sarcoid and cavities shows development of mycetoma with air-crescent sign.

inflammatory cell infiltrate within the wall of the cavity. 2.4. Semi-invasive aspergillosis
Fungal stains are rarely necessary as the mass of fungal ele-
ments is often recognizable by Hematoxylin and Eosin stain- Semi-invasive aspergillosis, also known as chronic necro-
ing alone (Fig. 7B). Because the fungus is growing in a tizing aspergillosis, is noted in patients with mild immunosup-
culture-like setting, diagnostic fruiting heads may be pression often including patients with diabetes mellitus, chronic
encountered in mycetoma (Fig. 7C). malnutrition, alcoholism, or chronic steroid therapy. Pre-existing
P. Panse et al. / Radiology of Infectious Diseases 3 (2016) 192e200 197

Fig. 7. A. Mycetoma characterized by a cystic cavity with a thickened fibrotic wall and a central ball of fungal elements. B. Fungal elements are easily identified on
routine staining within the fungal mass. C. Fruiting body characteristic of Aspergillus flavus seen in a mycetoma.

pulmonary pathology, most commonly COPD, may put the pa- thickening, endobronchial nodules and obstructive pneumonitis
tient at risk [18]. Patients present with long standing fever, cough can all be seen on imaging (Fig. 8 C and D).
and malaise. Treatment consists of antifungal therapy.
Pathologic features
Radiologic features
Semi-invasive aspergillosis is characterized by colonization
Imaging manifestations on X-ray and CT are non-specific and of preexisting spaces, often dilated airways, with associated
may mimic tuberculosis. As the name “chronic necrotizing invasion of the mucosa and resulting necro-inflammatory tis-
aspergillosis “ suggests, areas of consolidation often go on to sue reaction (Fig. 9). The airway lumen often has a mixture of
necrose centrally forming cavities (Fig. 8A and B) which may or fungal elements and necrotic debris compared to the pure
may not contain a mycetoma [21]. Slowly progressive consoli- fungal mass of mycetoma. The hallmark is the identification of
dations, nodules, cavitation, pleural thickening, bronchial wall invasion of the mucosa with resulting granulomatous

Fig. 8. 35-year-old male with diabetes mellitus, rheumatoid arthritis, gastroparesis and long-term steroid therapy. Axial CT images displayed in lung windows
demonstrate a cavity with adjacent ground-glass opacity and septal thickening. Pleural thickening and tree-in-bud nodules are noted. Radiographic findings and
biopsy compatible with semi-invasive aspergillosis. C, D Axial CT images showing semi-invasive aspergillosis with thick-walled cavity, ground-glass opacity,
nodularity and airway thickening.
198 P. Panse et al. / Radiology of Infectious Diseases 3 (2016) 192e200

transplant), patients on immunosuppressive chemotherapy, and

end-stage AIDS [22]. This manifestation of Aspergillus infection
can be rapidly fatal and prompt initiation of antifungal therapy
and, if possible, reversal of immunosuppression is critical.
Invasive aspergillosis can present with 2 different forms
depending if the predominate feature is invasion of the airways
or the blood vessels. Airway invasive aspergillosis is less com-
mon than angio-invasive aspergillosis and presents clinically as
tracheobronchitis, bronchiolitis or bronchopneumonia [23].
Angio-invasive aspergillosis invades the walls of the medium-
sized pulmonary arteries with resultant hemorrhage; this form
in particular carries significant morbidity and mortality.

Radiologic features

Fig. 9. Semi-invasive aspergillosis showing an airway with extensive luminal Plain radiographic findings in invasive aspergillosis are
proliferation of fungal elements and necrotic debris. There is focal invasion of generally nonspecific. Thickening of the airways, consolida-
the respiratory mucosa (arrow). tion, and nodules may be seen in the airway invasive form
inflammation. In this setting the fungus is often obvious and while the angio-invasive form usually presents with scattered
fungal stains are only necessary if fungal elements are not nodular and mass-like areas of consolidation. On CT findings
identified on H&E sections. of airway invasive disease remain non-specific and prospective
diagnosis may not be definitive. Airway thickening, secretions,
2.5. Invasive aspergillosis peribronchial consolidation (large airway involvement) and
centrilobular tree-in-bud nodules (small airway involvement)
Invasive aspergillosis is seen in the setting of profound are often seen [23]. The classic CT finding of angio-invasive
immunosuppression, especially neutropenia. Patients at risk for aspergillosis is the “halo-sign” which is characterized by
invasive Aspergillus infection include those on prolonged high- nodules and areas of nodular consolidation with surrounding
dose steroids, transplant patients (especially bone marrow ground glass opacity (Fig. 10AeE). The halo sign (arrows

Fig. 10. (A, B) Axial CT scan in immunosuppressed patient shows airway thickening, peribronchial consolidations, numerous nodules with surrounding ground-glass
opacity compatible with invasive aspergillosis (C, D). Mass in the left lower lobe with “halo sign” suggestive of angio-inasive aspergillosis (confirmed on pathology).
(E) Coronal reconstruction CT shows mass in the left upper lobe (arrows) in an immunosuppressed patient most compatible with angio-invasive aspergillosis.
P. Panse et al. / Radiology of Infectious Diseases 3 (2016) 192e200 199

Fig. 11. A. Hallmark lesion of invasive aspergillosis including a pulmonary artery (bracketed by the arrows) and numerous fungal elements (arrowhead) invading
through the vessel wall. B. Large areas of tissue necrosis are often encountered in invasive disease (upper portion of lung parenchyma necrotic). C. Grocott's
methenamine silver stain highlighting the fungal elements invading though a pulmonary artery. D. Miliary aspergillosis characterized by multiple necrotic nodules
randomly distributed throughout the lung parenchyma.

Fig. 10E) is non-specific and may be seen in other fungal (Fig. 11B). Fungal stains can highlight the organisms within
infections, hemorrhagic metastasis, Kaposi's sarcoma or the wall of vessels (Fig. 11C). Miliary aspergillosis is also
granulomatosis with polyangiitis [10]. considered a form of angio-invasive aspergillosis. In miliary
disease numerous similarly sized nodules are randomly
Pathologic features distributed throughout the lung parenchyma (Fig. 11D). The
nodules consist of infarct like necrosis with associated in-
Angio-invasive aspergillosis is defined by the presence of flammatory debris. In some cases the inflammation will have a
fungal elements invading through the arterial wall within tis- granulomatous appearance. Fungal stains often highlight
sues (Fig. 11A) [24]. This often results in extensive tissue fungal elements at the center of these necrotic nodules, pre-
necrosis and necrotic debris with neutrophilic inflammation sumably a result of hematogenous spread.

Table 2
Condition Synonyms Radiographic findings Pathologic findings
Allergic Bronchopulmonary Saprophytic aspergillosis Finger-in-glove Mucoid impaction of bronchi
aspergillosis (ABPA) Central bronchiectasis Allergic mucin
High attenuation mucoid impaction Eosinophilic pneumonia
Bronchocentric granulomatosis
Acute and chronic bronchiolits
Aspergilloma Mycetoma Mass in a cavity Mass of fungal elements
Air crescent sign Preexisting space or cavity
Thickened fibrotic wall
Semi-invasive Aspergillosis Chronic necrotizing Consolidation Extensive colonization of airways
aspergillosis Cavity with fungal elements
Tree-in-bud nodules Patchy areas of invasion of the
respiratory mucosa
Invasive Aspergillosis (Angio-invasive or Angio-invasive: Halo sign Infarct-like necrosis
Airway-invasive) Airway-invasive: airway Necro-inflammatory debris
thickening, tree-in-bud Fungal elements invading through the vessel walls
200 P. Panse et al. / Radiology of Infectious Diseases 3 (2016) 192e200

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