Aspergilloma
A pulmonary aspergilloma, also known as chronic pulmonary aspergillosis, is a human infectious disease of the lung caused by the colonization of a cavity by a fungus of the genus Aspergillus, most commonly Aspergillus fumigatus. The spores are transmitted through the air and are not contagious between individuals. It is a frequent complication of tuberculous cavities, which are themselves the primary sequelae of pulmonary tuberculosis, and correspond to localized lung tissue destruction. The cavities of pulmonary tubercles are poorly equipped to defend against Aspergillus infection, allowing the fungus to proliferate and form a pseudo-tumor that partially fills the cavity. It is estimated that more than 370,000 people worldwide develop an aspergilloma each year.
Several forms of aspergilloma exist, with varying severity and symptoms depending on the patient's overall health. Aspergillomas are distinguished from other Aspergillus infections by their localized nature. They are categorized based on their size and the degree of underlying lung destruction. The primary complication is bleeding, which leads to expectoration of blood, sometimes life-threatening. Diagnosis is based on a combination of radiological findings and fungal identification. Treatment is either medical, using antifungals, or surgical.
History
The genus Aspergillus was first described in 1729 by Italian botanist Pier Antonio Micheli. The first description of a human aspergilloma is attributed to John Hughes Bennett in 1842, though this attribution has been questioned. In 1847, Theodor Sluyter reported the first confirmed case of diffuse human aspergillosis, and in 1855, German physician Friedrich Küchenmeister provided the first autopsy description of an aspergilloma developed in an excavated bronchial carcinoma. Aspergillomas in tuberculous cavities were first described in 1856. Their radiological description was not established until 1938, and lesion classification was refined in 1952. The first antifungal treatment trials began in 1959, and surgical treatment was developed in the same decade.Overview
Causative organisms
Aspergillus fumigatus is a saprophytic soil fungus, highly prevalent, and one of the most prolific spore producers in the air. Its spores, measuring 2–3 µm in diameter, are small enough to reach the pulmonary alveoli and numerous enough that humans inhale several hundred daily. These spores are typically cleared by the immune system and only become pathogenic under certain conditions.While all fungi in the Aspergillus genus are potentially pathogenic, Aspergillus fumigatus accounts for 90% of human pulmonary infections. These infections are categorized into several types: allergic bronchopulmonary aspergillosis, invasive aspergillosis, and aspergilloma. Unlike diffuse infections such as invasive aspergillosis and allergic bronchopulmonary aspergillosis, aspergillomas are localized infections characterized by fungal growth within a cavity. Aspergillus sinusitis is another form, where the fungus develops in a natural sinus cavity of the face.
Predisposing conditions
While diffuse Aspergillus infections typically affect immunocompromised patients, colonization of a pulmonary cavity leading to aspergilloma formation primarily occurs in immunocompetent individuals with underlying chronic lung disease. Aspergillomas are not contagious between humans, as transmission occurs via inhaled air.Aspergillomas predominantly develop in tuberculous cavities; between 17% and 25% of patients with such cavities also have an aspergilloma. Since the 1980s, this proportion has decreased in Europe. In 2010, 15% of UK patients with aspergilloma had a history of pulmonary tuberculosis, compared to 93% in Korea. Other, less common mycobacterial infections also predispose to aspergillomas.
While the frequency of tuberculous cavities has decreased in developed countries by the late 20th century due to improved management of pulmonary tuberculosis, some tuberculosis patients remain at high risk. Globally, tuberculosis remains the primary risk factor for aspergillomas in the early 21st century, particularly in cases of global immune deficiency or lung destruction. Aspergillomas are the main sequelae of pulmonary tuberculosis: in 2007, 7.7 million people worldwide had pulmonary tuberculosis, with an estimated 372,000 developing at least one aspergilloma, primarily in Southeast Asia, the Pacific, and Africa. Aspergillomas in these patients are often underdiagnosed, mistaken for non-bacillary pulmonary tuberculosis or pulmonary fibrosis. Any tuberculosis patient with hemoptysis should be considered to have an aspergilloma.
Beyond tuberculosis, other lung diseases can lead to cavity formation where aspergillomas may develop. In HIV-positive patients, pneumocystosis is the second most significant risk factor after tuberculosis. In immunocompetent patients, chronic obstructive pulmonary disease, emphysema, and bronchial dilation are the main risk factors apart from tuberculosis. Pulmonary sarcoidosis, though rare, is complicated by aspergilloma in about 6% of cases. Major thoracic surgeries also increase risk. Approximately 3.6% of patients undergoing lobectomy for lung cancer develop an aspergilloma months or years later.
Pathophysiology
Formation of tuberculous cavities
A cavity is a hollow space within the lung parenchyma. Cavities are a common complication of pulmonary tuberculosis, appearing after primary infection.Tuberculous bacilli initially form nodules called granulomas, which are surrounded by lymphocytes and macrophages to contain the infection. Granulomas may resolve without scarring or progress to cavities, though the underlying mechanisms are not fully understood. The remnants of destroyed macrophages form the bulk of caseous necrosis at the granuloma's center. In some patients, this necrosis liquefies, creating an environment conducive to bacilli proliferation. Proteolytic enzymes erode the fibrous capsule surrounding the granuloma, and the liquid center may drain, replaced by air from the bronchi. When a tuberculous cavity communicates with the bronchial tree, bacilli dissemination in exhaled air increases contagiousness. The high bacilli load in cavities also promotes resistance to anti-tuberculous drugs. Once the liquefied necrosis is cleared, the granuloma's periphery persists around an empty, infection-prone cavity.
Composition of an aspergilloma
An aspergilloma appears as a spherical pseudo-tumor, often termed an "aspergillar ball" or "aspergillar truffle". It consists of fungal filaments embedded in a proteinaceous polysaccharide matrix. Sporulating structures line the aspergilloma.Several clinical forms of chronic pulmonary aspergillosis exist, which may overlap:
- Simple pulmonary aspergilloma, where a typical aspergilloma is suspended in a lung cavity, often asymptomatic, with no radiological progression over 3 months, and sometimes negative serology;
- Complex pulmonary aspergilloma, where one or more cavities contain aspergillomas, with clinical symptoms and radiological progression;
- Chronic pulmonary aspergillosis with fibrosis, where at least two lung lobes are destroyed by a complex aspergilloma;
- Aspergillar nodule, where the aspergilloma forms in healthy parenchyma rather than a cavity;
- Subacute invasive aspergillosis, in immunocompromised patients, where invasive aspergillosis progresses over months, creating cavities and nodules.
Mechanism of aspergilloma formation
The mechanisms underlying aspergilloma formation are poorly understood and remain debated.Spore adhesion to the respiratory epithelium, forming a biofilm, is the first step. Spores in contact with bronchial epithelium and alveoli produce enzymes, particularly proteases, that degrade nearby tissue proteins, especially elastin and collagen. Contact with spores causes epithelial desquamation and the release of pro-inflammatory cytokines. Locally produced interleukins contribute to aspergilloma formation, with certain genetic variations promoting complex aspergillomas, alongside the host's genetic immune profile. The resulting desquamation and inflammation reduce the epithelial barrier's effectiveness, facilitating Aspergillus infection.
Clinical manifestations
Aspergillomas are often asymptomatic, discovered incidentally on a chest X-ray or computed tomography performed for other reasons.Hemoptysis is the most common clinical sign. It affects 54–87% of patients and is massive in 10% of cases. The mechanism triggering bronchial vessel erosion is poorly understood; it may be mechanical, due to the aspergillar mass rubbing against the cavity wall, or chemical, due to local toxin production. Some suggest that anastomoses between bronchial and pulmonary vessels may contribute. The risk of hemoptysis becomes significant when the cavity exceeds 2 cm in diameter.
Another common symptom is a productive wet cough. Other symptoms are non-specific and may relate to the underlying lung disease, making it difficult to attribute them solely to the aspergilloma.
The annual mortality rate for aspergilloma patients is 5–6%. Up to 26% of patients die from massive hemoptysis.
Diagnostic investigations
Mycological diagnosis
Pathogen identification
Identifying the specific Aspergillus strain can be achieved through various methods. Testing sputum samples is often uninformative due to the high abundance of spores in the air, which can contaminate samples. Sputum analysis should include at least three separate samples to increase the likelihood of identifying the pathogen. Identification via bronchial fibroscopy is far more specific; direct examination looks for mycelial filaments, and culture seeks the strain itself. Cultures are grown on Sabouraud agar with antibiotics or malt extract agar incubated at 30 °C.Molecular detection via PCR is more sensitive than culture and requires only one sample. Biopsy of lesions, typically surgical or via EBUS, offers the highest sensitivity and specificity for mycological diagnosis but is more invasive.
Galactomannan, a complex sugar produced by the fungus, can be detected in sputum. Its antigen may also be detectable in blood.
Immunologically, the A. fumigatus antigen can be sought in sputum. The presence of anti-Aspergillus antibodies in blood, detected via serology, is critical for diagnosis. Serology distinguishes recent from past infections and differentiates simple bronchial colonization from true infection. A negative serology can rule out an aspergilloma in doubtful cases.