Pulmonary aspergillosis can be caused by various Aspergillus species, predominantly Aspergillus fumigatus. Aspergillus fumigatus often colonizes the upper respiratory tract. The immunity has a significant impact on the type of clinical aspergillosis. If the immunity is normal, allergic bronchopulmonary aspergillosis and Aspergillus-related allergic pneumonia may occur. When the immunity is extremely low, invasive pulmonary aspergillosis may occur.
Etiology
Aspergillus is widely present in nature, and its spores are widespread in the air. In autumn, winter, and rainy seasons, there are more Aspergillus in the stored moldy straws. Inhaled Aspergillus spores does not necessarily cause disease. Massive inhalation may cause acute tracheobronchitis or pneumonia. Aspergillus endotoxins cause tissue necrosis, and the lesions may be infiltration, consolidation, cavity, bronchitis, or miliary diffuse lesions.
Clinical manifestations
Clinically, pulmonary aspergillosis can be divided into invasive pulmonary aspergillosis (IPA), chronic pulmonary aspergillosis (CPA), and allergic bronchopulmonary aspergillosis (ABPA).
Invasive pulmonary aspergillosis
IPA is the most common pulmonary aspergillosis, with severely damaged lung tissue, treatment resistance, and high mortality. Invasive pulmonary aspergillosis is mostly localized granuloma or extensive suppurative pneumonia, accompanied by abscess formation. The lesion presents acute coagulative necrosis, accompanied by necrotizing vasculitis, thrombosis, mycotic embolus, and even pleural involvement. The symptoms are mostly dry cough and thoracodynia. Some patients have hemoptysis. In case of extensive lesion, tachypnea, dyspnea, and even respiratory failure may occur. Chest x-ray shows multiple wedgy, nodular, massive opacities or cavities based on the pleura. Some patients have typical chest CT manifestations of halo sign in the early stage; that is, pulmonary nodular opacity (edema or hemorrhage) is surrounded by hypodense opacity (ischemia); and crescent sign in the late stage. Some patients may have central nervous system infection.
Chronic pulmonary aspergillosis
CPA is mostly manifested by symptoms of chronic wasting disease such as recurrent or long-term malaise, emaciation, and anorexia, accompanied by non-specific symptoms such as chronic cough, unexplained hemoptysis, and chest tightness. It is difficult to diagnose through clinical symptoms. Insidious onset and slow progression result in imperceptibility in clinical practice. In general, patients only seek medical attention when they have hemoptysis or acute exacerbation, and there is high rate of missed diagnosis and misdiagnosis.
Different types of CPA have various clinical manifestations.
Simple pulmonary aspergilloma
The clinical manifestations of pulmonary aspergilloma are not specific, and some patients may have inapparent symptoms. The most prominent clinical symptom is recurrent intermittent hemoptysis. Most patients with pulmonary aspergilloma mainly present with little hemoptysis, while few patients may have fatal massive hemoptysis, the latter is most common in post-tuberculosis pulmonary aspergillosis. Chest CT shows a spherical structure in a single cavity. The lesion is subrounded, with clear boundaries and homogeneous density, and calcification can occur. There is an arcuate air-containing lucent area between the aspergilloma and the cavity wall. The aspergilloma can change and move with the change of body position (Monod sign). The aspergilloma is not enhanced on contrast-enhanced scan. Chest imaging changes are relatively stable.
Chronic cavitary pulmonary aspergillosis (CCPA)
Patients with CCPA often present with subacute symptoms such as cough, thoracodynia, and little hemoptysis. Some patients also have symptoms analogous to those in tuberculosis, such as fever, chills, diaphoresis, and emaciation. Different from simple aspergilloma, CCPA shows one or multiple cavities containing one or multiple aspergillomas or irregular contents on chest CT, often accompanied by thickening of the adjacent pleura. Chest imaging changes can progress slowly.
Chronic fibrosing pulmonary aspergillosis (CFPA)
Extensive pulmonary fibrosis involves at least two lung lobes, resulting in severe impairment of the lung function. In addition to clinical manifestations of CCPA, there is also tachypnea or dyspnea, especially after exercise. Imaging examination shows reduced volume of the damaged lung lobes with severe pulmonary fibrosis, significantly thickened adjacent pleura, and aspergilloma in the involved lung lobes.
Aspergillus nodules
Most patients with aspergillus nodules are asymptomatic and are usually found through chest imaging. Aspergillus nodules are a less common form of CPA, and have single or multiple nodules with or without cavity formation. The disease cannot have characteristic imaging manifestations, resembles tuberculoma and lung tumor in imaging, and can only be diagnosed by histopathology.
Subacute invasive pulmonary aspergillosis (SAIA)
SAIA usually has invasive characteristics and is characterized by chronic cough, expectoration, and fever. About 15% of SAIA patients have hemoptysis. The imaging manifestations of SAIA are diverse, including cavities, nodules, progressive consolidation with cavity formation, aspergilloma or irregular contents in the cavity, peripheral consolidation, centrilobular nodules, and thickening of the adjacent pleura. Aspergillomas or contents are not enhanced on contrast-enhanced scan, and the cavity wall can be enhanced.
Allergic bronchopulmonary aspergillosis
ABPA is a kind of airway hyperresponsiveness disease mostly caused by Aspergillus fumigatus. After individuals allergic to Aspergillus inhale some spores, Bronchioles are obstructed, causing transient atelectasis and wheezing, as well as recurrent migratory infiltration in the lungs. Patients have wheezing, chills, fever, malaise, irritating cough, brownish yellow purulent expectoration, and occasionally bloody expectoration. There are numerous eosinophils and Aspergillus hyphae in the sputum and positive culture of Aspergillus fumigatus. Asthma attack is its prominent clinical manifestation, and bronchodilators are generally ineffective. There are peripheral blood eosinophilia, serum IgE > 1,000 IU/ml, positive Aspergillus immediate skin reaction, positive serum Aspergillus fumigatus IgG antibody, and positive serum Aspergillus-specific IgE. Chest x-ray or CT shows unilateral or bilateral central bronchiectasis (bronchi in the inner 2/3 of the lung field) and transient pulmonary infiltration, manifested by transient consolidation or atelectasis in the upper lobe, ground-glass opacity with mosaic sign, and mucoid impaction.
Diagnosis
The diagnosis of pulmonary aspergillosis depends on tissue culture and histopathological examination. Microscopic examination shows acute-angle branched, septate, non-pigmented hyphae with a diameter of about 2 - 4μm. Aspergillus grows in the sterile tissue or body fluid culture. If the fungal components of respiratory specimens from sputum, bronchoalveolar lavage fluid, and bronchial brushing in microscopy are Aspergillus, the culture is positive, or CT or x-ray examinations of the lungs, brain, and sinuses show characteristic changes, and the patient is an immunosuppressed host, aspergillosis should be suspected. In immunosuppressed hosts, smears, cultures, and/or antigen assays of bronchoalveolar lavage fluid have good specificity and positive predictive values. In antigen skin test with Aspergillus extracts, allergic patients have an immediate reaction, indicating the presence of IgE antibodies. Serum IgE may be significantly increased in patients allergic to Aspergillus. Aspergillus galactomannan assay in blood, urine, cerebrospinal fluid, and bronchoalveolar lavage fluid, and PCR assay of Aspergillus DNA in blood are also helpful for the diagnosis of this disease, and dynamic observation of its changes is more valuable for diagnosis.
Treatment
Voriconazole is preferred for the treatment of invasive pulmonary aspergillosis. The treatment regimen is 6 mg/kg in the first day followed by 4 mg/kg once every 12 hours; after the condition improves, the dose is orally 200 mg once every 12 hours. The course of treatment is at least 6 - 12 weeks. Isavuconazole has similar efficacy to voriconazole, with better safety and tolerability. Posaconazole injection or enteric-coated tablets are recommended. Due to the emergence of new antifungal drugs, amphotericin B deoxycholate is no longer preferred currently. Amphotericin B lipid complex has less nephrotoxicity and is mainly suitable for patients with existing renal function impairment or nephrotoxicity after the application of amphotericin B, and the dose is 5mg/(kg·d).
Echinocandins such as caspofungin and micafungin in combination with voriconazole or isavuconazole can be used as salvage therapy for drug-resistant, refractory, or progressive IPA. Echinocandins can also be alternative in patients intolerant to azoles.
When chronic pulmonary aspergillosis has complications such as aggravated respiratory symptoms or hemoptysis and has serological and imaging progression, antifungal treatment is recommended. The preferred regimen is oral itraconazole 200mg twice a day or voriconazole 150 - 200mg twice a day, and therapeutic drug monitoring (TDM) should be conducted to achieve the best therapeutic effect and avoid adverse reactions. In case of resistance or adverse reactions to itraconazole or voriconazole, oral isavuconazole or posaconazole can be administered as alternative drugs. Intravenous infusion of echinocandins or amphotericin B and its derivatives is the second-line treatment in case of failure, resistance, and intolerance to triazoles.
The treatment of pulmonary aspergilloma is mainly to prevent life-threatening massive hemoptysis. If conditions permit, surgical treatment should be performed. Bronchial artery embolization can be used to treat massive hemoptysis. Intrabronchial and abscess cavity injection of antifungal drugs or oral itraconazole may be effective.
Glucocorticoids are preferred for the treatment of acute ABPA. The treatment plan is prednisone orally 0.5mg/kg once a day initially, followed by once every other day 2 weeks after treatment. In chronic ABPA, the dose is 7.5 - 10 mg/d, and the course of treatment depends on the situation and generally lasts for 3 months. Antifungal combination treatment helps to reduce the dose of systemic hormones and the risk of invasive Aspergillus infection. In patients with confirmed Aspergillus sensitization through Aspergillus-specific IgE examination and persistent wheezing after adequate treatment or dependence on oral hormones, antifungal treatment can be considered. Antifungal treatment regimen is itraconazole orally 200mg/d, for more than 16 weeks. Voriconazole and posaconazole are also effective. β2 receptor agonists or inhaled glucocorticoids can be administered if needed.