Aspergilloma

Etiology

Aspergillus species are ubiquitous saprophytes in the environment. Aspergillus is a filamentous fungus that thrives in moist conditions, such as soil, plants, and decaying vegetation. However, the conditions that promote the dispersion of spores include dry, dusty environments, hay barns, and compost sites. A fumigatus is the most common human pathogen, although A niger, A flavus, and A oryzae have also been reported to cause human disease.

Risk factors for Aspergillus-mediated lung disease (including aspergilloma and chronic cavitary pulmonary aspergillosis) are:

• Pulmonary tuberculosis
• Nontuberculous mycobacterial infection
• Cystic fibrosis
• Chronic bronchiectasis
• Pneumoconiosis
• Post-infarct pulmonary cavity
• Post-radiation pulmonary cavity
• Sarcoidosis
• Bronchial cysts and bullae
• Chronic lung abscess
• Lung malignancy
• Ankylosing spondylitis
• Allergic bronchopulmonary aspergillosis

Chronic Debilitating Conditions Affecting Local Bronchopulmonary Defense

• Malnutrition
• Chronic obstructive pulmonary disease
• Chronic liver disease

Immunosuppression

• Post-solid organ transplant
• Stem cell transplant
• Chemotherapy
• Neutropenia
• Prolonged corticosteroid use
• HIV
• Primary immunodeficiency syndromes

Aspergilloma and CCPA most commonly occur in immunocompetent individuals with preexisting structural lung disease. The worldwide prevalence is highest among those with residual lung cavities due to TB, with approximately 10% of preexisting tuberculous lung cavities developing into aspergillomas.[6][7] In addition to TB, individuals with nontuberculous mycobacteria, chronic obstructive pulmonary disease, and lung cancer are also at high risk. SARS-CoV-2 pneumonitis has recently been identified as a cause of aspergilloma, with several reported cases (see Image. HRCT Chest Scan Showing Aspergilloma With SARS-CoV-2 Pneumonitis Features).[8][9]

Epidemiology

The prevalence of CPA varies significantly across regions. In developed countries such as the United States, the prevalence is lower than 1 case per 100,000 individuals. However, in some African nations, the prevalence can be as high as 42.9 per 100,000 individuals. This difference is largely attributed to the higher prevalence of tuberculous pulmonary cavities in populations from resource-poor regions of the world.[10] The incidence of aspergilloma in patients with CPA is about 25%. The estimated global 5-year period prevalence is 18 cases per 100,000 individuals,[11] which translates to a global burden of 1.2 million patients. Higher incidence and prevalence are reported in Africa, the Western Pacific, and Southeast Asia.[11] 

In resource-rich countries with a low prevalence of TB, the primary risk factor for CPA is chronic obstructive pulmonary disease. Isolated aspergilloma without preexisting parenchymal disease is much rarer, reported at 0.13%. Interestingly, although invasive Aspergillus disease is more common in patients with primary or acquired immunodeficiency, the incidence is relatively uncommon in HIV-infected patients.[12]

Pathophysiology

Human lungs are constantly exposed to airborne fungi, which are a common component of the external environmental microbiome. Among all fungal organisms, A fumigatus and A niger are frequent colonizers. Aspergillus spores primarily enter the respiratory tract and external auditory canal. These filamentous organisms rapidly multiply and become clinically significant in patients with pre-existing lung disease or systemic immunodeficiency.

Aspergillomas thrive in poorly drained, avascular cavitary spaces. Within these cavitary airspaces, the organism attaches to the wall with its conidia, germinates, and triggers an inflammatory response. Both aspergilloma and CCPA typically do not invade the surrounding lung tissue. Instead, the organism and inflammatory debris form an amorphous mass known as an aspergilloma. In the early stages, ulceration or an irregular, cobblestoned cavity wall or floor may be the only pathological finding. As the disease progresses, the aspergilloma becomes mobile within the cavity, which can be observed on imaging.

Hemoptysis is the most common clinical manifestation in symptomatic patients, with the bleeding typically originating from a bronchial vessel. This is usually secondary to:

• Direct invasion of the capillaries in the wall lining.
• Endotoxin release from the organism.
• Mechanical irritation of exposed vessels within the cavity.
• A rapidly growing cavity that erodes into the pleural surface and intercostal arteries, leading to massive, often fatal hemoptysis, which is highly challenging to control.

An aggressively growing aspergilloma increases the risk of exposure and erosion into the broader pulmonary arterial system. Triggered by hypoxia, inflammation, and architectural distortion, the opening of the pulmonary and bronchial arterial anastomotic plexus becomes a target for erosion, leading to hemoptysis. As previously noted, clinical features may overlap. Multiple fungal balls can develop, especially in patients with chronic cystic bronchiectasis or multicystic bullous disease. In some cases, aspergilloma may form within the bronchial tree (endobronchial aspergilloma) or the pleural space in chronic empyema.[13]

Histopathology

The organism is characterized by septate hyphae with dichotomous branching and long conidiophores that carry numerous spores at their tips. In histological specimens, aspergilloma appears as a network of inflamed, swollen septate hyphae, fibrin, blood clots, cellular debris, and mucous residues. The central core is often necrotic. Although the lining of a simple aspergilloma may consist of ciliated epithelium, it is more commonly composed of pseudostratified columnar or metaplastic squamous epithelium. Depending on the severity of the inflammation and the progression of the condition, the walls may show signs of chronic granulomatous inflammation, lymphoid follicles, endarteritis, ulceration, and fibrosis.

History and Physical

A general understanding of predisposition is essential for recognizing specific forms of Aspergillus-mediated disease. Individuals with atopy or a tendency toward hypersensitivity are more prone to obstructive bronchopulmonary aspergillosis. Immunocompromised patients are at higher risk for invasive Aspergillus infections, while aspergilloma and other forms of CPA are more common in immunocompetent individuals with preexisting lung disease. However, there is an overlap between these predisposition categories. Patients with aspergilloma can develop a hypersensitivity response similar to allergic bronchopulmonary aspergillosis.[14] Additionally, a chronic aspergilloma that remains unchanged over months to years can progress to CCPA, CFPA, or invasive infection.

Aspergilloma and CCPA can present with a wide range of clinical symptoms, from asymptomatic colonization of a preexisting lung cavity to potentially fatal hemoptysis. Additionally, patients with aspergilloma may exhibit symptoms related to their underlying lung disease, such as bullous emphysema, bronchiectasis, cavitary TB, cystic fibrosis, lung tumors, or sarcoidosis. According to various case series, hemoptysis is the most common clinical manifestation, occurring in 54% to 87.5% of cases.[15][16] Massive hemorrhage occurs in approximately 30% of patients. Notably, the size of an aspergilloma, lesion complexity, underlying lung disease, or prior minor hemoptysis do not reliably predict the risk of massive bleeding.[17][18] Although fever is rare, patients with CCPA may experience cough, chest pain, malaise, and weight loss. If the organism invades the surrounding lung parenchyma, recurrent pneumonia, chronic cough, or pulmonary fibrosis may develop.[19] 

Evaluation

A presumptive diagnosis of aspergilloma and CCPA is made based on characteristic radiographic features in patients with known underlying lung disease. Occasionally, it may be discovered as an incidental finding in asymptomatic individuals. Once identified radiographically, additional diagnostic criteria include the presence of Aspergillus organisms in lower airway cultures obtained through bronchoalveolar lavage (BAL), a positive serum or BAL galactomannan test, and the detection of serum Aspergillus-specific immunoglobulin-G (IgG) antibodies. 

Patients with a simple aspergilloma are not immunocompromised and typically experience minimal or no symptoms related to the fungal mass. Aspergilloma is often suspected based on findings from chest x-rays or computed tomography (CT) scans in patients being evaluated for symptoms related to underlying pulmonary diseases. For example, aspergillomas may be suspected in individuals with preexisting TB lung cavities, bronchiectasis, tumors, or chronic lung abscesses based on radiographic evidence. Alternatively, hemoptysis resulting from an aspergilloma may also prompt further evaluation. The European Society for Clinical Microbiology and Infectious Diseases, in collaboration with the European Respiratory Society and the Infectious Diseases Society of America, has published comprehensive guidelines for the diagnosis and management of CPA, including aspergilloma and CCPA.[1][4]

X-Ray

A chest x-ray is typically the initial diagnostic test for patients presenting with symptoms. An x-ray may reveal upper lobe–predominant cavitation, wall thickening, scarring, and, in some cases, a rounded mass-like opacity within the cavity.

Computed Tomography Scan

A CT scan provides greater detail and reveals characteristic features, including:

• The appearance of a solid spherical lesion within the cavitary space.
• A halo sign, indicating an inflammatory reaction in the cavity wall.
• An air crescent sign, where the fungus ball is separated from the cavity wall along part or all of its circumference (also seen in lung abscess, hydatid cyst, and granulomatosis with polyangiitis).
• The Monod sign, which is characterized by a shift in the fungus ball’s position within the cavity when the patient changes position during imaging (see Image. CT Scan of the Lung Showing Aspergilloma Mass With Monod Sign).

CT imaging helps define the thickness of the cavity wall, architectural distortion, and inflammation in the surrounding parenchyma and pleura. This also provides insights into the relationship between the aspergilloma and nearby blood vessels, as well as the nature of neovascularization in both the lung parenchyma and parietal pleura. The upper lobe of either lung is the most common location for aspergilloma, although the superior segment of the lower lobe can also be involved.

Radiographic Features

Radiographic features of CCPA may show areas of consolidation along with one or multiple cavities of varying wall thickness, often containing an aspergilloma. Adjacent pleural thickening is commonly observed. Simple aspergilloma can progress to CCPA, and both conditions can evolve into the fibrotic and subacute invasive forms of CPA.[20]

Radiographs provide a presumptive diagnosis of aspergilloma and CCPA. The presence of Aspergillus organisms in sputum is not diagnostic, as the fungi are ubiquitous and can colonize the airway without causing disease. However, in patients with characteristic radiographic findings, identifying Aspergillus organisms in BAL further supports the diagnosis. Conversely, the absence of organisms in the culture does not rule out the diagnosis. The role of molecular tests performed during bronchoscopy remains uncertain.

Aspergillus-specific IgG antibodies in serum provide strong presumptive evidence of CPA when characteristic radiological features are present. However, patients who acquired their infection in regions such as Pakistan, where A flavus and A fumigatus are predominant, may have negative serum serology tests unless species-specific assays are used.[21] The galactomannan antigen assay, targeting a polysaccharide component of the fungal cell wall, demonstrates high specificity. Typically, the sensitivity of the galactomannan antigen is higher in BAL fluid compared to serum. False-positive results may occur in patients receiving piperacillin-tazobactam, while false-negative results can arise with high-dose steroid therapy. IgG antibodies against Aspergillus species, detected by precipitin assay, are positive in over 90% of cases. Aspergillus IgG titers are typically elevated in patients with CPA and gradually decrease (although rarely becoming undetectable) with treatment.[22][23] 

Aspergilloma and CCPA can coexist with active lung conditions, such as neoplasms and other infectious diseases.[24][25][26] These additional etiologies should be considered when evaluating patients with suspected aspergilloma and CCPA.

Treatment / Management

The management of CPA lacks standardized guidelines, as several aspects remain controversial due to the unpredictable nature of the infection and limited clinical experience.[13] Most published studies are small case series or anecdotal reports that do not clearly differentiate between the various types of CPA. The primary treatment goals are alleviating symptoms, preventing and minimizing hemoptysis episodes, and preventing progression to pulmonary fibrosis.

Approximately 10% of simple aspergillomas undergo spontaneous regression, while a significant number can lead to massive hemoptysis.[2] The ability to predict the severity of hemoptysis based on factors such as symptomatic versus asymptomatic presentation, aspergilloma size, extent, and associated underlying lung disease is limited.[2] Data suggest that the incidence and severity of hemoptysis are similar between simple and complex aspergillomas, with complex aspergilloma likely encompassing CCPA, although its definition remains vague.[2] An episode of minor hemoptysis predicts subsequent massive hemoptysis in approximately 30% of patients.[27] (B2)

Surgical resection, long considered the gold standard, can be associated with high morbidity and mortality, while antifungal therapy is often considered of limited value. The experience (or lack thereof) of the surgical and medical team can significantly impact the management outcome, which should be considered when evaluating published case series. Although guidelines have been developed, controversy persists regarding management approaches, especially for asymptomatic patients.[1][2][4] The Infectious Diseases Society of America recommends conservative, ongoing observation for asymptomatic patients with a single, stable aspergilloma. If symptoms like hemoptysis develop, resection is advised unless contraindicated. Perioperative or postoperative antifungal therapy should be considered if there is a risk of surgical spillage. In high-risk surgical candidates and those reluctant to undergo surgery, prolonged courses of triazoles are recommended.(A1)

Although surgical resection is considered the mainstay of therapy, it is important to recognize that not all patients with aspergilloma are suitable surgical candidates due to poor general health, low pulmonary reserve, and the presence of extensive disease. Before the development of triazoles and echinocandins, systemic antifungal therapy had a limited role in management. However, more recent experience with triazole and echinocandin therapy has demonstrated therapeutic benefits in patients deemed inoperable.[28] In patients with symptomatic CCPA, oral triazole therapy is now considered the standard of care.[1] Guidelines recommend an initial 4- to 6-month course of oral triazole therapy, with the duration extended for those who demonstrate slow or minimal response. Despite the lack of robust long-term data, lifelong triazole suppression may be worth considering, though no firm recommendations are currently recognized.

An alternative form of antifungal therapy should be considered for patients who do not respond to or are intolerant of oral triazole therapy. Triazole resistance can develop with prolonged administration. Systemic administration of amphotericin B desoxycholate has not shown significant benefits, likely due to its associated toxicities. In small published studies, intravenous (IV) liposomal amphotericin and IV echinocandins have demonstrated clinical benefits and should be considered for patients who do not respond, are intolerant, or have triazole-resistant organisms.[1] 

Intracavitary installation of antifungal agents should be considered in nonsurgical candidates who experience recurrent hemoptysis or patients not responding to systemic antifungal therapy. Depending on the cavity size, location, the patient's pulmonary status, and the medical team's experience, intracavitary antifungal installation can be performed via an endobronchial or percutaneous catheter.[29][30][28] These methods should be considered short-term therapeutic options, with potential complications including pneumothorax and cough. Transbronchial removal of aspergilloma, a nonsurgical approach, has recently shown promise in selected patients.[31][32] However, its application and value in management await further evaluation.(B2)

In patients with mild-to-moderate hemoptysis, oral tranexamic acid may be administered to help stabilize clot formation.[33] Antifungal therapy can also prevent the recurrence of hemoptysis. In cases of massive hemoptysis, bronchial artery embolization by interventional radiology has proven successful in 50% to 90% of cases, although recurrence rates remain high.[34] Subsequent antifungal therapy should be initiated following embolization. In some instances, embolization of the internal mammary, subclavian, and lateral thoracic arteries may be necessary to control hemoptysis. However, embolization of arteries near the origins of the spinal and vertebral arteries should be avoided to prevent spinal cord infarcts and paralysis.[35] Recent data from centers with experienced surgical teams report operative mortality between 0.9% and 3.3%, with morbidity rates ranging from 23.6% to 33.3%.[36][37] (A1)

The decision to proceed with surgery should be tailored to the individual, taking into account several factors, including:

• The patient's overall functional status and pulmonary reserve
• The experience of the surgical team
• Presenting symptoms, such as asymptomatic, cough, chest pain, and weight loss
• The presence or absence of hemoptysis and the degree of its severity
• An indeterminate diagnosis and the potential presence of an underlying neoplasm

Surgical approaches for aspergilloma include lobectomy, pneumonectomy, segmentectomy, cavernectomy, and pleurectomy. Video-assisted thoracoscopy can be a valuable option for select patients.[22] Surgical complications may include bronchopleural fistula, pneumonia, empyema, respiratory failure, hemorrhage, and death. Surgical removal of a simple aspergilloma is typically considered curative. However, if there is intraoperative spillage of the cavity contents or if the entire aspergilloma cannot be removed, a postoperative course of antifungal therapy is recommended.[1] However, the duration of antifungal treatment in the postoperative setting is empiric and should be individualized.

Removal of a simple aspergilloma is considered curative. However, complex aspergillomas and CCPA often require prolonged courses of antifungal therapy, and a complete cure may not be achievable. In these cases, the goal is to stabilize the disease and reduce hemoptysis. Follow-up should include chest CT scans every 3 to 6 months initially. If radiographic findings stabilize or improve, the frequency of scans can be reduced.[38] Serial Aspergillus-IgG serology should also be monitored, with a decline in antibody titers indicating a positive response to therapy. 

Differential Diagnosis

A space-occupying lesion within a lung cavity may be attributed to various conditions, including:

• Primary lung malignancy
• Metastatic disease
• Aspergilloma
• Hydatid cyst
• Lung abscess

The differential diagnoses of CCPA include:

• Active tuberculosis
• Nontuberculous mycobacteria
• Histoplasmosis
• Coccidioidomycosis
• Actinomycosis
• Neoplasm

Prognosis

The prognosis of aspergilloma and CCPA is difficult to quantify due to their unpredictable course, the presence of associated lung diseases, and the patient's functional status. Spontaneous resolution occurs in approximately 10% of simple aspergilloma cases. The recent availability of triazole and echinocandin antifungal agents in symptomatic patients has shown benefits in about 65% of those treated. Similar benefits have been observed with intracavitary instillation of antifungals. However, the impact of these treatments on long-term prognosis remains unclear, and symptomatic improvements do not necessarily correlate with life expectancy.

The mortality rate for patients experiencing massive hemoptysis from any cause has historically been reported as high as 38%.[39] Whether this figure applies to current management strategies for aspergilloma and CCPA remains uncertain. After successful bronchial artery embolization, the recurrence of hemoptysis occurs in 19% to 55% of cases.[28] The effect of new antifungal agents and nonsurgical management on the prognosis of aspergilloma and CCPA requires further investigation.

Complications

Hemoptysis is the most common and feared complication. Additional complications related to the underlying lung disease are expected. Potential complications may arise from the use of antifungal agents, whether administered systemically or through intracavitary instillation. Intraoperative and postoperative complications, as outlined above, should be carefully considered when assessing preoperative risks for each patient. The natural history of simple aspergilloma and CCPA is poorly understood, with the conditions either remaining relatively stable or progressing to more extensive and invasive lung pathology.