Introduction

Endobronchial aspergilloma (EBA) is a rare manifestation of pulmonary infection with Aspergillus spp. Colonization of the respiratory tract begins with accidental inhalation of infectious conidia released by these ubiquitous filamentous fungi. Spores that successfully evade the innate immune system, particularly alveolar macrophages, can germinate and potentially develop endobronchial mucoid impaction via intraluminal growth without invasion into pulmonary tissues. Comprised of hyphae, mucus, and cellular debris, the massive fungus ball can lead to obstructive pneumonitis in large airways, manifesting with symptoms of cough, dyspnea, hemoptysis, or weight loss. It is distinct from pulmonary aspergilloma, the most common form of Aspergillus infection, which forms in areas with parenchymal deformities such as cavitary lesions from prior tuberculosis infection or scarred lung tissue in sarcoidosis, bronchiectasis, or emphysema [1]. EBA associated with foreign bodies and underlying malignancy have also been reported [2, 3]. Radiographically, it can mimic or mask endobronchial tumors [4, 5]. Bronchoscopic findings can reveal yellowish-white plaques to whitish nodules [6]. It has the potential for progression to tracheobronchitis, bronchomediastinal fistulization, and acute respiratory failure [7, 8]. Mortality up to 48% has been approximated [9]. To date, there are 28 reported cases of pulmonary aspergilloma in English literature and optimal treatment therapies are lacking. Increasing reports of this disease entity mandates its reclassification under non-invasive forms of pulmonary aspergillosis.

Spectrum of pulmonary aspergillosis

Pulmonary aspergillosis generally affects immunocompromised patients and those with underlying lung disease or recent instrumentation due to impaired clearance of inhaled conidia. Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus are typical culprits. Posited as a continuum, there are presently four main categories of infection: invasive pulmonary aspergillosis (IPA), subacute invasive pulmonary aspergillosis (SIA), allergic bronchopulmonary aspergillosis (ABPA), and pulmonary aspergilloma. The specific disease state depends on the immune status of the individual and the presence of structural abnormalities of the lung. Impacting those with severe immunodeficiency, IPA is an infection that extends across tissue planes and involves vasculature, leading to tissue necrosis. In contrast, those with chronic lung disease can develop SIA which is comparatively more indolent, localized, and does not demonstrate tissue invasion. This is thought to be related to an incomplete host immune response which is not able to eliminate the infection. On the other hand, ABPA is a hypersensitivity reaction to Aspergillus colonization of the airways that almost exclusively affects those with atopy, asthma, or cystic fibrosis. Pulmonary aspergilloma is the most common form of Aspergillus infection and is easily discoverable on diagnostic imaging (“air-meniscus sign”) in patients with pre-existing lung cavities or scarred lung tissue. Typically found in the upper lobes, it can be subclassified as simple aspergilloma when the pathogen is encased in a thin-walled cavity within preserved pulmonary tissue and as complex aspergilloma if wall becomes thickened with development of fibrosis and adhesions in the lung parenchyma. Hemoptysis can occur in as many as 73% of patients [10]. The fungus ball can move with change in body positioning [10]. EBA is a distinct entity from that of pulmonary aspergilloma in that it does not involve pre-existing parenchymal distortion. Rather, it has been suggested that endobronchial lesions such as foreign body objects, broncholith, lung cancer, and suture material of anastomosis site after pulmonary resection can serve as nidus for Aspergillus colonization.

Method

A descriptive analysis was performed on articles on PubMed database that contained the key word “endobronchial aspergilloma.” Four articles were excluded as they were not available in the English format. A total of 28 cases were obtained. The descriptions of these cases are summarized in Table 1.

Table 1 Descriptive summary of the location, gross description and radiologic findings of available cases of endobronchial aspergilloma on PubMed
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Clinical description

In a descriptive analysis of 28 patients [1,2,3,5,6,7,8,11,14,15,16,17,18], EBA appears to disproportionately affect males (71.4%, 20/28) with median age of 58. Approximately 70% of these cases were from Asia with 25% from the USA. These demographics are not dissimilar from an analysis performed by Huang et al. of 17 cases [11]. There may not be a clear association with smoking since just a third of patients have a smoking history (32.1%, 9/28). Many patients were found to have current or prior history of pulmonary disease: pulmonary tuberculosis (28.5%, 8/28), underlying lung cancer (32.1%, 9/28) or history of cancer of any origin (25%, 7/28), lung resection for early-stage lung cancer or pneumothorax (7.1%, 2/28), chronic lung disease (17.8%, 5/28), and history of foreign body aspiration (3.6%, 1/28). Among the reviewed cases, eight were severely immunocompromised (28.5%, 8/28). The clinical manifestations of pulmonary aspergillosis vary widely from asymptomatic to cough (productive or non-productive), dyspnea, malaise, weight loss, chest pain, and fever. Hemoptysis and cough are the most frequent symptoms, occurring in 57.1% of patients (16/28).

Vital signs and physical examination for EBA are non-specific. Reduced breath sounds with adventitious breath sounds such as wheezing or rhonchi in areas that correlate with pulmonary opacification are typically heard. There may be a slight predilection for involvement of the left lung (64.3%, 18/28). Involvement of the left upper lobe (35.7%, 10/28), left lower lobe (17.8%, 5/28), and right main bronchus (17.8%, 5/28) are the most common.

Radiographic findings

Radiographically, on chest x-ray (CXR) imaging, it may present as localized or diffuse nodular opacities. Monod’s sign, wherein a mobile endobronchial lung mass can change its radiographic location depending on the patient’s body positioning, can occasionally be observed with pulmonary aspergilloma but has not been reported in any cases of EBA to date. Similarly, in pulmonary aspergilloma, an air-crescent sign (see ESM1 [19]) correlating with obstructive pneumonitis has been described but was not observed in cases of EBA. CXR can also appear normal with limited infection. Computed tomography (CT) of the chest may further characterize the mass; however, it remains non-diagnostic. Descriptions of EBA have included a soft tissue mass with or without obstruction and tracheal or bronchial wall thickening with lobar and/or segmental atelectasis. A few cases have noted underlying shadow which was suspicious of an occult malignancy. As it cannot be distinguished from that of lung malignancy, some patients may undergo positron emission tomography (PET) which can be false positive due to surrounding inflammatory response. Table 1 is a descriptive summary of the location, gross description, and radiologic findings of available cases of endobronchial aspergilloma on PubMed.

Diagnosis

Diagnosis of EBA cannot be made radiographically or with non-invasive tests such as serology or culture of bronchial washings. A thorough history is necessary to assist with exclusion of other differentials including malignancy, foreign body aspiration, parasitic infection, or mucous plug formation. While it is uncertain if all cases have tested for serum Aspergillus antigen because it has been incidentally discovered histopathologically, it has only been positive in 7.1% (2/28) of cases. Serological analyses and bronchial washings are unreliable; they were negative in a number of studies despite obvious identification of Aspergillus infection on biopsied specimens. There appears to be strong association with malignancy: one quarter of patients have underlying malignancy. Reported cancers include clear cell, endobronchial, neuroendocrine, lung, or rectal adenocarcinoma; hepatocellular carcinoma; and small cell and carcinoid tumor. In the present study, all patients were diagnosed incidentally with analysis of bronchoscopic specimens with histopathological confirmation and/or culture.

Bronchoscopy findings vary from endobronchial yellowish-white necrotic material-plaques to whitish nodules, pseudomembranes, mucosal surface ulcerations, and purulent exudates. Fistulae are rare. A requirement of EBA confirmation is the identification of an intraluminal mass with or without necrotic tissue visible on bronchoscopy. Histopathological examination demonstrates typical findings of Aspergillus spp.: separated hyphae with dichotomous branching at 45° angle. A. fumigatus is by far the most common pathogen cultured.

Treatment

Current treatment regimens remain to be optimized though piecemeal resection of the mycetoma with bronchoscopic techniques with the addition of systemic antifungals and their combinations, such as amphotericin B, voriconazole, itraconazole, and caspofungin, have been reported as efficacious [7, 8]. Due to concerns about poor penetration of systemic antifungals in lung tissue, these medications have been administered endobronchially or via inhalation, though its efficacy remains dubious [12, 13]. Pneumonectomy, partial lobectomy, wedge resection, partial lung decortication, and cavernostomy can be considered as last resort options reserved for severe or recurrent infection, but are limited by the need for adequate post-resection lung reserve volumes and the need for localized disease.

In those with underlying cancer, pulmonary lobotomy was performed after completing a course of antifungal medications with symptomatic resolution and without complications during outpatient follow-up [3, 10].

Discussion

EBA is a rare disease entity that remains unclassified under non-invasive forms of pulmonary aspergillosis. It is essentially the development of a massive mycetoma in large airway without invasion noted on histopathological examination. It has the propensity to lead to more severe infection, including obstructive pneumonitis, tracheobronchitis, and acute respiratory failure. It is distinct from pulmonary aspergilloma in that it does not form within lung cavities formed from other disease states such as pulmonary tuberculosis or in damaged lung tissue. It does however appear to be associated with underlying malignancy in up to one quarter of patients. Reported malignancies with superimposed EBA are extremely diverse and include clear cell, endobronchial, neuroendocrine, lung, or rectal adenocarcinoma; hepatocellular carcinoma; and small cell and carcinoid tumor. Concerns have been raised as the occurrence of EBA can mask and/or delay the diagnosis of underlying malignancy. PET imaging if utilized early in diagnostic work-up can even mimic malignancy as it can provide indeterminate results due to localized inflammation at the site of infection. Due to scarce reports of this rare entity, treatment therapies have not been optimized. Reports have varied widely from supportive therapy to partial lobectomy with or without systemic antifungals. EBA should be considered as a differential diagnosis for endobronchial mass, particularly in Asians, those with a history of malignancy and/or recent or treated pulmonary tuberculosis.

Conclusion

Although EBA is extremely rare, it should be considered in the differential diagnosis of endobronchial masses in immunocompromised patients. There is a potential for the disease entity to progress to tracheobronchitis and fulminant respiratory failure. As such, early detection with bronchoscopy, biopsy, and culture is required to confirm pulmonary aspergillosis. Serological and bronchial lavage specimens are unreliable. Current treatment regimens remain to be optimized, though piecemeal resection of the mycetoma with bronchoscopic techniques with the addition of systemic antifungals and their combinations, such as amphotericin B, voriconazole, itraconazole, and caspofungin, have been reported as efficacious. Pneumonectomy, partial lobectomy, wedge resection, partial lung decortication, and cavernostomy can be considered as last resort options reserved for severe or recurrent infection, but are limited by the need for adequate post-resection lung reserve volumes and localized disease.