Imaging Spectrum in Chronic Pulmonary Aspergillosis

ABSTRACT.

Chronic pulmonary aspergillosis (CPA) is a life-threatening respiratory fungal infection that is almost exclusively seen in patients with preexisting structural lung disease with no or mild immunosuppression. The clinical presentation and imaging findings are varied and often pose a diagnostic challenge; and the disease is often present for a long time before being correctly diagnosed. High-resolution chest computed tomography is the imaging modality of choice because it helps identify various forms of CPA, which can range from a simple aspergilloma and chronic cavitary form, to the subacute invasive and end-stage fibrotic form. The knowledge of the imaging features of this disease cannot be overemphasized because it can assist the clinician in reaching at an early diagnosis and timely initiation of appropriate antifungal therapy, thereby improving patient management and treatment outcome. Moreover, imaging also plays a pivotal role during follow-up in patients of CPA to assess the treatment response. In the current review, we present an illustrative review of radiologic patterns seen in various forms of CPA.

INTRODUCTION

Aspergillus is a common saprophytic colonial fungus, ubiquitously found in nature, that affects susceptible hosts when inhaled. Aspergillus fumigatus is the most common species responsible for the majority of respiratory infections. Depending on the underlying immune status, the fungus may cause disease through any of the following mechanisms: fungal sensitization, allergic response, saprophytic colonization, and/or frank invasion of the lung parenchyma. Hence, it is now regarded as a semicontinuous spectrum of allergic, noninvasive, and invasive forms.^1,2 The present classification, recognizes three major forms of pulmonary aspergillosis: allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and invasive pulmonary aspergillosis (IPA).³ In this article, we describe the imaging spectrum of CPA.

CPA is a relatively rare form of the disease seen almost exclusively in patients with preexisting structural lung disease and affects patients who have no or minimal immune compromise. The common primary underlying lung diseases in order of frequency for CPA are sequelae of pulmonary tuberculosis (TB), nontuberculous mycobacterial (NTM) infections, and ABPA, whereas chronic obstructive pulmonary disease (COPD), pneumothorax, and lung cancer are the other causes.⁴ Underlying risk factors also have geographic variation. While post-TB lung disease continues to be a major risk factor for CPA in developing countries, NTM is now emerging as a common risk factor in countries nonendemic for TB and is recognized as a predictor of mortality in CPA patients.^5,6 The clinical and radiological pattern of CPA is varied; the diagnosis is often missed or delayed leaving the disease to remain in the body for long periods. The importance of knowledge of the imaging features of this disease cannot be overemphasized because it can assist the clinician in reaching an early diagnosis and timely institution of appropriate antifungal therapy, thereby improving CPA patient management and treatment outcome. Moreover, imaging also plays a pivotal role during follow-up in patients of CPA to assess the treatment response.⁷

This imaging review focuses on the radiologic features of various forms of CPA, outlining the entire imaging spectrum.

CHRONIC PULMONARY ASPERGILLOSIS

CPA is a saprophytic form of Aspergillus infection, affecting immunocompetent patients or those with a mild degree of immunocompromise. The latter group includes patients with diabetes, alcohol abuse, chronic malnutrition, or those on chronic steroid therapy of < 10 mg/day. All these conditions contribute to the development of CPA in two ways: by promoting colonization of pre-existing cavities by Aspergillus, and by causing a varying degree of immunosuppression in the host.^4,8–11

The clinical features include productive cough, dyspnea, and hemoptysis of a long duration, although some patients may remain asymptomatic for years. Histopathologically, it is characterized by the fungal hyphae colonizing the damaged lung with no definite evidence of invasion except in the semi-invasive form. The diagnosis of CPA is made by a combination of clinical, imaging, and laboratory findings.^11–13 The latest task force guidelines described by European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and European Respiratory Society (ERS), as well as those developed by Infectious Diseases Society of America (IDSA) define the following diagnostic criteria for CPA: 1) presence of disease for at least 3 months (chronic pulmonary symptoms or chronic illness) in patients with one or more underlying pulmonary disorders; 2) direct evidence of Aspergillus infection (on microscopy/culture/biopsy) or an indirect evidence (positive immunological assays); 3) imaging (preferably computed tomography [CT] scan) demonstrating one or more cavities with or without fungal ball; pericavitary infiltrates and pleural thickening; 4) exclusion of an alternate diagnosis.^10–13

Microbiological or immunological evidence of Aspergillus can be established either by positive polymerase chain reaction, antibody detection (IgG), or galactomannan assay in serum/bronchoalveolar lavage (BAL) or histopathologically by biopsy.^11–15 Serum galactomannan assay is primarily used to diagnose subacute invasive aspergillosis with BAL having higher diagnostic yield.¹⁶

The closest mimicker of CPA is Mycobacterium tuberculosis or nontuberculous mycobacterial infection, which may precede or coexist with CPA. Active TB is characterized by miliary/centrilobular nodules, lymphadenopathy, and pleural effusion; the presence of cavitation, intracavitary soft tissue, and pleural thickening favors CPA¹⁷ while their absence generally rules out CPA in patients who have been treated for TB.¹⁸ Nevertheless, because the sequelae of pulmonary TB is a major risk factor for CPA and can have similar clinical and radiological features (cavitation and fibrosis), it is now being recommended to test for Aspergillus-specific IgG routinely in patients who present with recurrent cough, hemoptysis, or weight loss after treatment of pulmonary TB.¹⁹ The preexisting cavities can also be infected with other organisms such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Pseudomonas aeruginosa. Thus, all these infections must be ruled out by sputum examination, culture, or other microbiological tests. The other differentials of CPA could be cavitating lung neoplasm, vasculitides, infarcted lung, and other endemic fungal infections (e.g., histoplasmosis, coccidioidomycosis).¹⁸

Although Aspergillus fumigatus is the most common cause of CPA, other species, including flavus and niger, may also be the causative agents in few cases.^20–22 The latter species are, however, associated with allergic rhinosinusitis and ABPA/ IPA, respectively.^1,18

Depending on the host susceptibility, CPA can manifest in any one of the following forms: simple aspergilloma, chronic cavitary pulmonary aspergillosis (CCPA), chronic fibrosing pulmonary aspergillosis (CFPA), semi-invasive or subacute invasive aspergillosis (SAIA), and Aspergillus nodule(s).³

The majority of patients of CPA show overlapping clinical and radiological features between these subtypes and it is often difficult to categorize a case into one particular subtype. The noninvasive forms, including simple aspergilloma, Aspergillus nodule, and CCPA, are mainly found in immunocompetent individuals and have an indolent course,¹¹; whereas SAIA is characterized by rapid progression, local invasion, and parenchymal destruction.²³

Chest radiograph is the initial screening imaging modality and can demonstrate cavities, bronchiectasis, soft tissue within the cavity, nodules, and volume loss/lung fibrosis. High-resolution CT is the investigation of choice for better delineation of the cavities and cavity wall invasion, intracavitary soft tissue, pleural thickening, and lymphadenopathy. The utility of magnetic resonance imaging (MRI) thorax in CPA has not been much investigated. Despite MRI being a radiation-free modality, it has a limited role due to its low signal-to-noise ratio in lungs, high susceptibility artifacts at the lung–tissue interface, cardiac/respiratory motion artifacts, and poor sensitivity in detecting smaller nodules or pericavitary infiltrates.²⁴ Recent advances include the development of immuno–positron emission tomography MRI, along with target-specific radiolabeled antibodies in detecting the Aspergillus fumigatus related respiratory infections noninvasively, particularly in patients of IPA.²⁵

Supplemental Figure 1 denotes a diagrammatic representation describing various subtypes of CPA as seen on CT chest.

SIMPLE ASPERGILLOMA

Aspergilloma, or “simple aspergilloma” is caused by saprophytic colonization of a preexisting cavity by the fungus and is also called “fungal ball.” Pathologically, it consists of hyphae, cellular debris, and mucus in a preformed cavity or bronchiectasis.²³ The most common underlying lung diseases include TB, non-TB mycobacteria, and sarcoidosis.²³ The other predisposing conditions might include a bronchogenic cyst, pulmonary sequestration, cavitated pulmonary infarct, and pneumatoceles secondary to Pneumocystis jirovecii infection.^26–28

Although mostly single, these may be multiple and bilateral. Simple aspergilloma can be associated with other forms of CPA (excluding Aspergillus nodules) and often occur late in the disease course.¹¹

Clinically, these patients are mostly asymptomatic with no significant clinical progression over months. Few of these patients may present with hemoptysis, which occasionally could be massive and require treatment.^29,30

Chest radiograph shows air-filled cavity usually located in the upper lobes with intracavitary soft tissue. Also notable may be the changes of underlying structural lung disease such as bronchiectasis and lung architectural distortion.³¹

High-resolution CT thorax is the imaging modality of choice and typically depicts a well-defined soft tissue density mass contained within a lung cavity, with a characteristic Monod sign (air surrounding the aspergilloma in a preexisting cavity).^26,28 The cavity may be thin or thick walled and contain multiple soft tissue strands traversing through which are consistent with fungal hyphae.³² In the majority of the cases, the intracavitary mass is shown to be mobile on prone imaging, however, in a few cases, it may be fixed.³³ Thickening of the cavity wall and adjacent pleural thickening are subtle imaging pointers toward development of a simple aspergilloma on serial imaging.²⁹ Thus, the presence of a mobile air-filled mycelial meshwork in a preexisting cavity is usually supportive of the diagnosis (Figure 1, Supplemental Figure 2). The fungal balls may show dense calcifications within, but usually no enhancement is seen on postcontrast images.^34–36 CT bronchial angiography may be warranted in few patients presenting with life-threatening hemoptysis.³⁷

Figure 1.

Simple aspergilloma. Axial high-resolution computed tomography sections in 38-year-old male with post–primary tuberculosis. (A) Supine and (B) prone images showing mobile intracavitary contents (simple aspergilloma) in the left lower lobe.

The differential diagnosis of intracavitary fungal ball includes echinococcal cyst, lung abscess, hematoma, tubercular cavity with Rasmussen aneurysm, and cavitary bronchogenic carcinoma.^38–40

CHRONIC CAVITARY PULMONARY ASPERGILLOSIS

CCPA, previously known as complex aspergilloma, is the most common form of CPA. This is often characterized by the presence of multiple cavities with pulmonary/systemic symptoms and raised inflammatory markers.^41,42

The disease follows an indolent course with slow radiological progression in the form of development of new cavities, paracavitary infiltrates, and adjacent pleural changes over a few months. The disease may be difficult to differentiate from SAIA, with the latter following a relatively more rapid course.

On imaging, the hallmark features of CCPA are multiple thick-walled cavities with surrounding patchy areas of consolidation and adjacent pleural thickening. The cavities may or may not contain simple aspergilloma within.^1,37 Because TB is a great mimicker and risk factor of CPA, certain features such as presence of cavitation with aspergillomas, paracavitary consolidation, and pleural thickening should raise a red flag for the development of CPA in such patients, and microbiological evidence must be sought to reach at a conclusive diagnosis.^17,19

These findings are frequently asymmetric and mainly involve areas with preexisting lung disease.⁴¹ The cavities may enlarge and coalesce if the disease remains untreated and can progress to SAIA and ultimately CFPA^37,43 (Figure 2, Supplemental Figure 3).

Figure 2.

Chronic cavitary pulmonary aspergillosis. Axial high-resolution computed tomography sections of a 36-year-old male patient, a known case of chronic obstructive pulmonary disease who presented with chronic fatigue, breathlessness, and weight loss, shows parenchymal destruction of the right upper lobe with residual cavitary and bronchiectatic changes (red arrows). A cavity containing intraluminal simple aspergilloma is also seen (black arrow) in panel A.

SUBACUTE INVASIVE ASPERGILLOSIS

SAIA, or semi-IPA, acquires its name due to its locally invasive nature and subacute, rather than a chronic, indolent course.^{38–41,44–46}. It differs from the other forms of CPA in affecting mildly immunocompromised hosts, causing regional invasion and destruction of the lung parenchyma. This was previously also known as chronic necrotizing pulmonary aspergillosis. The susceptible hosts include patients with diabetes, malnutrition, corticosteroid use, connective tissue disorders, HIV infection, and COPD.

Clinically, patients present with chronic cough, weight loss, low-grade fever, and hemoptysis. Radiologically, features resemble CCPA except for rapid progression that is seen in the SAIA, and thus serial imaging is important for its diagnosis, which demonstrates rapidly increasing cavities, or patches of consolidation in contrast to CCPA, where the disease is more stable.

CT demonstrates areas of focal consolidation and mass-like lesions undergoing progressive cavitation, mainly affecting the upper lobes. Pathologically, there is pleural invasion by the hyphae, which may be seen as pleural thickening. Development of new pleural thickening and paracavitary infiltrates is an indicator of active disease. A small number of cases may be complicated by empyema and bronchopleural fistula, from where Aspergillus may be isolated.⁴¹ A definitive diagnosis is thus made by characteristic imaging features, exclusion of other diagnosis and biopsy evidence of invasion into the cavity wall. Due to its locally invasive nature, it warrants treatment on the same lines as IPA¹¹ (Figure 3, Supplemental Figure 4).

Figure 3.

Subacute invasive aspergillosis. Axial contrast-enhanced computed tomography sections (mediastinal window) in a 20-year-old woman who was on chronic low-dose steroids and presented with fever and exacerbation of shortness of breath; showed multiple peripherally enhancing cavities with internal necrosis and presence of intra-cavitary air-fluid levels (red arrows).

CHRONIC FIBROSING PULMONARY ASPERGILLOSIS

CFPA is often the end result of untreated CCPA.⁴⁷ It is characterized by extensive lung fibrosis with destruction of at least two lung lobes and considerable loss of pulmonary function.⁴¹ Patients have a prolonged illness, characterized by fever, night sweats, cough, and hemoptysis. Serological or microbiological evidence of disease is invariably present.

Radiological findings include gross volume loss of one or more lobes. CT often shows multiple cavities with surrounding fibrosis and lung architectural distortion. It can mimic any other end-stage fibrotic lung disease. The presence of simple aspergilloma within a few of these cavities may be the only clue that the end-stage lung fibrosis is due to underlying CPA (Figure 4).

Figure 4.

Chronic fibrosing pulmonary aspergillosis. Axial high-resolution computed tomography section in a 66-year-old woman with weight loss, hemoptysis, and chronic shortness of breath showing extensive fibrotic destruction of the left lung field with volume loss and ipsilateral mediastinal shift (red arrow).

ASPERGILLUS NODULES

Aspergillus nodules are one of the relatively simpler and unusual forms of CPA, characterized by one or more nodules on imaging. These patients have no significant underlying immunocompromise and are clinically asymptomatic.^41,48 Typically, this condition is characterized by single or multiple noncavitary nodules, measuring less than 3 cm in size. These may be round or have spiculated edges. Although there is no tissue invasion, necrosis and cavitation maybe seen in larger nodules.³⁸ It is a nonspecific finding, and the differential diagnosis may include rheumatoid nodules, metastases, cryptococcosis, or lung carcinoma.^49–53

The imaging features of various forms of CPA are summarized in Table 1. Figure 5 describes a proposed algorithmic approach in a patient suspected to have CPA.

Table 1.

Summary of various forms of chronic pulmonary aspergillosis

Subtype	Immune status	Clinical symptoms	Serological evidence		Basic radiologic feature	Salient feature
Simple aspergilloma	Immunocompetent	Minor/none	++	IgG precipitins	Fungal ball in preexisting cavity, associated cavitary lung parenchymal disease present	Simplest form
Chronic cavitary pulmonary aspergillosis	Immunocompetent	Pulmonary/systemic ++	++	IgG precipitins	Single/multiple cavities with intraluminal material/aspergillomas; associated structural lung disease present	Overt Radiologic progression +
Chronic fibrosing pulmonary aspergillosis	Immunocompetent	Pulmonary ++	++	IgG precipitins	Large cavities with fibrosis; associated lung parenchymal changes present	Untreated chronic cavitary pulmonary aspergillosis
Subacute invasive pulmonary aspergillosis	Mild degree of immune compromise	Systemic ++	++	Serum galactomannan assay	Cavitation/nodules/consolidation over a background of underlying lung disease	Progresses to invasive aspergillosis
Aspergillus nodule(s)	Immunocompetent	Minor/none	–	Tissue diagnosis required	Single/multiple nodules; may show cavitation	Mimics tuberculoma, malignancy

Figure 5.

Flowchart denoting a proposed imaging algorithm in a case of suspected chronic pulmonary aspergillosis.

Clinically and radiologically, there can be considerable overlap among patients harboring one or the other forms of CPA described here. If the degree of immunosuppression worsens in a patient with CCPA, radiologic and clinical progression into a relatively more invasive form like SAIA may be seen, which can eventually evolve into CFPA if left untreated.⁵⁴ However, patients may respond to antifungal treatment with the disease reversing into milder forms. Supplemental Figure 5 shows a diagrammatic representation of the overlap of various subtypes of CPA.

SAIA may also convert into frank IPA with increasing degree of immunosuppression. IPA and CPA usually have distinct features on imaging. Whereas CPA is characterized by multiple cavities, pleural thickening, and infiltrates, IPA radiologically presents as dense, well-circumscribed lesion(s) with or without a surrounding “halo” of ground-glass attenuation that may progress to cavitation and formation of an “air-crescent sign” on CT.⁵⁵

Treatment of CPA depends on the disease subtype and clinical profile. Asymptomatic simple aspergilloma does not require any treatment, whereas symptomatic patients with hemoptysis can be offered surgical resection for the same.⁵⁶ Oral azoles constitute the first-line therapy for patients of CPA, with itraconazole and voriconazole being the preferred drugs; and posaconazole and isavuconazole used as a salvage therapy.⁵⁷ SAIA, due to its semi-invasive nature, is treated just like IPA.^58–60 Imaging also helps in predicting treatment response in patients of CPA. Patients with bilateral disease, multilobar disease, and multiple aspergillomas on imaging are more prone to have relapses and thus carry a poor prognosis.^60,61 Also, a reduction in pleural thickening, intracavitary contents, and pericavitary infiltrates on follow-up imaging is associated with improvement.⁶²

CONCLUSION

CPA presents with a variable spectrum of imaging findings that depend on the underlying immune status of the patient. Because the clinical presentation of the disease is nonspecific and the awareness is limited, the diagnosis of CPA is often missed or delayed. Thus, the knowledge of salient radiological features of CPA is essential as it can help raise a red flag, warranting further clinical and immunological workup to reach at a definitive diagnosis and thus save lives by improving treatment outcomes.

Note: Supplemental table appears at www.ajtmh.org.