Pulmonary aspergillosis is a fungal infection caused by various species of Aspergillus, with Aspergillus fumigatus being the primary pathogen. A. fumigatus often colonizes the upper respiratory tract, and the type of pulmonary aspergillosis depends significantly on the patient’s immune status. For individuals with normal immunity, allergic bronchopulmonary aspergillosis (ABPA) or Aspergillus-related allergic pneumonia may develop. In cases of severe immunosuppression, invasive pulmonary aspergillosis (IPA) can occur.
Etiology
Aspergillus species are ubiquitous in the environment, and their spores are widely dispersed in the air. The concentration of spores is particularly high during autumn, winter, and rainy seasons, especially when stored grains or straw become moldy. Inhalation of Aspergillus spores does not necessarily lead to disease, but massive inhalation may cause acute tracheobronchitis or pneumonia. The endotoxins produced by Aspergillus can cause tissue necrosis, resulting in lesions that manifest as infiltrative, consolidative, cavitary, bronchitic, or miliary changes.
Clinical Manifestations
Pulmonary aspergillosis can be classified into three main types.
Invasive Pulmonary Aspergillosis (IPA)
IPA is the most common type, characterized by severe lung tissue destruction, difficulty in treatment, and a high mortality rate. It often manifests as localized granulomas or widespread suppurative pneumonia with abscess formation. Lesions show acute coagulative necrosis, necrotizing vasculitis, thrombosis, and fungal emboli, which may even involve the pleura. Common symptoms include dry cough and chest pain, with some patients experiencing hemoptysis. Extensive lesions may lead to dyspnea, respiratory distress, or even respiratory failure.
Chest X-rays often reveal multiple wedgy, nodular, or mass opacities near the pleura, sometimes with cavitation. On CT, typical early findings include the halo sign (a hypodense halo surrounding a pulmonary nodule due to edema or hemorrhage) and later the crescent sign (crescent-shaped air surrounding a retracted necrotic nodule).
Some patients may develop central nervous system (CNS) infections, presenting with neurological symptoms and signs.
Chronic Pulmonary Aspergillosis (CPA)
CPA typically presents with chronic symptoms such as fatigue, weight loss, and reduced appetite, often accompanied by chronic cough, unexplained hemoptysis, and chest tightness. The insidious onset and slow progression make it difficult to detect clinically. Many patients are only diagnosed when experiencing hemoptysis or acute exacerbations, leading to a high rate of misdiagnosis or missed diagnosis. CPA can be further divided into subtypes:
Simple Aspergilloma
Clinical symptoms are nonspecific, and some patients may be asymptomatic. The most prominent symptom is recurrent intermittent hemoptysis. Most patients present with mild hemoptysis, but a small number may experience life-threatening massive hemoptysis, which is most common in post-tuberculosis aspergilloma.
Chest CT shows a single cavity or cavitary structure containing a spherical mass. The lesion is round or oval, with well-defined margins and homogeneous density, sometimes with calcifications. A crescent-shaped air space between the aspergilloma and the cavity wall (Monod's sign) may be observed, and the aspergilloma may shift with changes in body position. Contrast-enhanced CT shows no enhancement of the aspergilloma, and the imaging findings are relatively stable.
Chronic Cavitary Pulmonary Aspergillosis (CCPA)
CCPA patients often present with subacute symptoms such as cough, chest pain, and mild hemoptysis. Some may exhibit symptoms similar to tuberculosis, including fever, chills, diaphoresis, and weight loss.
CT typically shows one or more pulmonary cavities containing one or more aspergillomas or irregular material, often with thickened pleura near the lesion. Imaging changes progress slowly.
Chronic Fibrosing Pulmonary Aspergillosis (CFPA)
Extensive pulmonary fibrosis involving at least two lobes leads to significant impairment of lung function. In addition to symptoms similar to CCPA, patients may experience dyspnea or shortness of breath, especially after physical activity.
Chest CT shows reduced lung volume in severely fibrotic lobes, marked pleural thickening, and aspergillomas within the affected lobes.
Aspergillus Nodules
Most patients with Aspergillus nodules are asymptomatic, and the condition is often discovered incidentally on imaging. Aspergillus nodules are a rare form of CPA, presenting as single or multiple nodules with or without cavitation. Imaging findings are nonspecific and may resemble tuberculomas or lung tumors. Definitive diagnosis requires histopathological confirmation.
Subacute Invasive Aspergillosis (SAIA)
SAIA typically exhibits invasive features, with symptoms such as chronic cough, expectoration, fever, and systemic manifestations. Approximately 15% of patients may experience hemoptysis.
CT shows diverse features, including cavities, nodules, progressive consolidation with cavity formation, aspergillomas or irregular material within cavities, and surrounding consolidation or small nodules. Pleural thickening near the lesion is common. Contrast-enhanced CT shows no enhancement of aspergillomas or cavity contents, but cavity walls may show enhancement.
Allergic Bronchopulmonary Aspergillosis (ABPA)
ABPA is a hypersensitivity reaction to Aspergillus fumigatus and is characterized by airway hyperreactivity. Inhalation of large amounts of spores in allergic individuals can lead to small airway obstruction, transient atelectasis, and asthma exacerbations, as well as recurrent migratory pulmonary infiltrates.
Symptoms include wheezing, chills, fever, fatigue, irritative cough, and expectoration of brownish-yellow purulent sputum, sometimes with blood. Sputum may contain abundant eosinophils and fungal hyphae, and cultures for A. fumigatus are positive. Asthma exacerbations are a hallmark of ABPA and are often refractory to conventional bronchodilators.
Laboratory findings include peripheral eosinophilia, serum IgE > 1,000 IU/mL, positive immediate hypersensitivity skin test for Aspergillus, positive serum A. fumigatus IgG and specific IgE antibodies.
Chest X-ray or CT may show central bronchiectasis (in the medial two-thirds of the lung fields) and transient pulmonary infiltrates, such as transient upper lobe consolidation or atelectasis, ground-glass opacities with a mosaic pattern, and mucus plugging, which may occur bilaterally.
Diagnosis
The definitive diagnosis of pulmonary aspergillosis relies on tissue culture (biopsy specimens from affected organs) and histopathological examination. Microscopically, Aspergillus hyphae are seen as colorless, septate filaments with acute-angle branching, measuring approximately 2-4 μm in diameter. Growth of Aspergillus species in sterile tissue or body fluid cultures is diagnostic. If fungal elements consistent with Aspergillus are identified in respiratory specimens (e.g., sputum, bronchoalveolar lavage fluid, or bronchial brushings) or if cultures are positive, combined with characteristic CT or X-ray findings in the lungs, brain, or sinuses, Aspergillus infection should be suspected, especially in immunocompromised hosts. Invasive pulmonary aspergillosis (IPA) in immunosuppressed patients can be diagnosed with high specificity and positive predictive value using bronchoalveolar lavage (BAL) smear, culture, and/or antigen detection.
For allergic patients, skin testing with Aspergillus antigens may elicit an immediate hypersensitivity reaction, indicating the presence of IgE antibodies. Serum IgE levels are significantly elevated in individuals allergic to Aspergillus. Tests for Aspergillus galactomannan antigen (GM test) in blood, urine, cerebrospinal fluid, or BAL fluid, as well as PCR for Aspergillus DNA in blood, are also helpful for diagnosis. Monitoring dynamic changes in these markers can provide further diagnostic value.
Treatment
Invasive Pulmonary Aspergillosis
The first-line treatment for IPA is voriconazole. The initial dose is 6 mg/kg on the first day, followed by 4 mg/kg once every 12 hours. Once the condition improves, treatment can be switched to oral voriconazole at 200 mg once every 12 hours. The treatment duration is at least 6-12 weeks. Isavuconazole has similar efficacy to voriconazole but offers better safety and tolerability. When using posaconazole, the intravenous formulation or delayed-release tablets are recommended.
Due to the availability of newer antifungal agents, amphotericin B deoxycholate is no longer the first choice. However, it remains a cost-effective option with good efficacy. Treatment should start with a low dose, such as 0.1 mg/kg dissolved in 5% glucose solution, administered slowly via light-protected intravenous infusion. The dose is gradually increased by 5-10 mg per day to reach the maximum tolerated dose (1-1.5 mg/kg/day), which is then maintained. The treatment duration and total dose are individualized based on the severity of the disease, response to therapy, underlying conditions, and immune status. Major side effects include chills, fever, palpitations, back pain, liver and kidney dysfunction, and refractory hypokalemia. However, moderate renal impairment during treatment is not necessarily an indication to discontinue the drug. Lipid formulations of amphotericin B (e.g., liposomal amphotericin B) reduce nephrotoxicity and are suitable for patients with pre-existing renal dysfunction or those who develop nephrotoxicity during treatment. The recommended dose is 5 mg/kg/day.
Echinocandins (e.g., caspofungin, micafungin) combined with voriconazole or isavuconazole can serve as salvage therapy for resistant, refractory, or progressive IPA. Echinocandins may also be used as alternative agents in patients intolerant to azoles.
Chronic Pulmonary Aspergillosis
For CPA patients with worsening respiratory symptoms, hemoptysis, or complications accompanied by serological and imaging progression, antifungal therapy is recommended. The first-line options are oral itraconazole (200 mg twice daily) or oral voriconazole (150-200 mg twice daily), with therapeutic drug monitoring (TDM) to achieve optimal efficacy and minimize adverse effects. If resistance or intolerance to itraconazole or voriconazole develops, isavuconazole or posaconazole can be used as alternatives. Intravenous echinocandins or amphotericin B and its derivatives are second-line treatments for cases where azole therapy fails, resistance occurs, or patients cannot tolerate azoles.
Aspergilloma
The primary goal of treating aspergilloma is to prevent life-threatening massive hemoptysis. Surgical resection is recommended when feasible. Bronchial artery embolization can be used to control massive hemoptysis. Intracavitary or intrabronchial administration of antifungal agents, as well as oral itraconazole, may also be effective.
Allergic Bronchopulmonary Aspergillosis
The first-line treatment for acute ABPA is glucocorticoids. Prednisone is initiated at a dose of 0.5 mg/kg/day and tapered to alternate-day dosing after two weeks. For chronic ABPA, glucocorticoid doses are typically 7.5-10 mg/day. The treatment duration depends on the patient’s condition and usually lasts for three months or longer. Combining antifungal therapy with glucocorticoids can help reduce systemic steroid use and lower the risk of invasive aspergillosis. For patients with confirmed Aspergillus-specific IgE sensitization and persistent asthma symptoms despite adequate treatment or those who are steroid-dependent, antifungal therapy may be considered. Itraconazole (200 mg/day orally for more than 16 weeks) is the preferred antifungal agent. Voriconazole and posaconazole are also effective options. Β2-agonists or inhaled glucocorticoids may be used as adjunctive therapies when necessary.