Fungal infections have been on the rise during recent years due to the increased number of immune-compromised hosts and the abuse of antibiotics. The respiratory system is exposed to the external environment and is vulnerable to fungal infections. According to the statistics of the Beijing Union Hospital, the morbidity from fungal infections in 2003 nearly quadrupled that of the 1990's in China. Cases of aspergillosis have been increasing since the early 1990's, with deep infection seen mostly in cancer patients, patients with immunodeficiency or recipients of organ transplantation, most frequently infiltrating the lung and bronchial tree.1 We have observed a group of patients with airway aspergillosis, who are most likely to have airway obstruction, and we termed the condition pseudomembranous necrotizing tracheobronchial aspergillosis (PNTA).2 Treatment of PNTA is difficult.3,4 To gain more information on the condition, we retrospectively analyzed the clinical data of 16 PNTA patients who were pathologically or etiologically confirmed from Jan. 2000 to Jan. 2009 in our hospital.
The 16 patients were hospitalized in the Department of Respiratory Diseases from Jan. 2000 to Jan. 2009 (Table 1). The demographic information, clinical symptoms and signs, imaging findings, primary diseases, possible inducement, infection location, etiology, treatment and prognosis of patients were retrospectively analyzed. The clinical properties were summarized to guide the future diagnosis and treatment of the disease.
Extensive airway pseudomembrane formation, caused by necrotic tissue and metabolites of aspergillus, was found in all the 16 patients by bronchoscopy. Airway obstruction or constriction was diagnosed when the airway was ≥50% of the original caliber. A diagnosis was made when samples of the lesion (biopsy, cytology or bronchial fluid) met one of the following two criteria: (1) Biopsy pathology of the lesion confirmed aspergillus infection, with the culture of a type of aspergillus. (2) Lesion smear or bronchial fluid positive for aspergillus hyphae and spores, with the positive culture of a type of aspergillus.3,5
Assessment of outcomes
The outcome of patients was assessed according to the relief of clinical symptoms and the improvement of lesions under the bronchoscope, and they were divided into the following four results: (1) cure: clinical symptoms disappeared, normal image findings, bronchial mucosa is smooth under bronchoscope, total relief of airway stenosis, and elimination of pathogenic fungus; (2) improved: relief of clinical symptoms, improved image findings, decreased lesion area under bronchoscope, and partial relief of airway obstruction; (3) stable: with no noticeable improvement of the clinical symptoms, and no apparent changes in image findings and bronchoscopy examination; (4) progressive: symptoms aggravated, lesions increased by imaging and bronchoscopy examination, worsened airway obstruction or seeding of fungal infection.3,6
From January 2000 to January 2009, a total of 18 612 patients underwent bronchoscopic examination in our department, and 16 were confirmed to have PNTA, with a morbidity of 0.86%. The 16 patients included 12 males and 4 females, with a male to female ratio of 3:1. The youngest patient was 36 years old at diagnosis and the oldest one was 73 years old, with a mean of (54.06±11.5) years old. Eleven patients were 50-70 years old.
Fourteen patients (87.5%) had progressive dyspnea, 12 (75.0%) had irritable cough, six (37.5%) had intermittent hemoptysis, five (31.3%) had fever, and three (18.8%) had sputum containing white or grayish yellow pseudomembranous substance. Thirteen (81.3%) had rhonchus on lung auscultation, four (25.0%) had moist rales, three (18.8%) had end expiration wheezing sound. All the 16 patients had primary diseases, including nine (56.3%) with primary pulmonary and tracheobronchial tumors, five (31.3%) with tracheobronchial involvement secondary to non-pulmonary tumors, two (12.5%) with chronic obstructive pulmonary disease (COPD) terminal stage (right lung transplantation). The most common cause included local radiotherapy for 10/16 (62.5%), repeated chemotherapy for 7/16 (43.8%) and recurrent intervention therapy by bronchoscope for 4/16 (25.0%), long-term exposure to broad-spectrum antibiotics in 3/16 (18.8%) and long-term exposure to immunosuppressants for 2/16 (12.5%).
All 16 patients underwent chest X-ray and CT examination. Chest X ray showed no abnormal changes in 12 cases (75.0%), and only four (25.0%) had obstructive pneumonia at the distal end of the airway. Chest CT showed infiltrated and thickened tracheobronchial walls, narrowed lumen and loose new growth appeared in the airway tubes in 7/16 patients (Figure 1). Four patients (25.0%) had obstructive pneumonia at the distal end of the lesion and atelectasis, and three (18.8%) had pleural effusion.
All the 16 patients received bronchoscopic examination under local anesthesia after signing the informed consent form. Patients with dyspnea had enough oxygen inhalation to ensure an oxygen saturation rate higher than 90%. The bronchoscopic findings of PNTA can include congestion of the tracheal and the bronchial wall, edema, and a grayish white moss-like substance attached on the wall of the trachea and bronchus. The moss-like substance was closely attached to the tissues and was different from caseous necrotic tissues; it was rubbery and was hard to exfoliate, forming a pseudomembranous membrane and greatly narrowing the tube (Figure 2 ).
Lesion location in the airway and etiology distribution
We found that the lesions were mainly located in the right main bronchus and trachea, with 10/16 (62.5%) involving the right main bronchus, 9/16 (56.3%) involving the trachea, 3/16 (18.8%) involving the left main bronchus, and only 1 lesion (6.3%) involving the segmental bronchus and below the bronchus. Four lesions (25%) involved the trachea and main bronchus at the same time. Fourteen patients (87.5%) had pathological samples obtained by bronchoscope, and 10 cases (62.5%) were positive by smear and/or bronchial fluid. The distribution of aspergillus was dominated by Aspergillus fumigatus (62.5%, 10/16), followed by Aspergillus flavus (12.5%, 2/16), Aspergillus niger (12.5%, 2/16), Aspergillus terreus (6.25%, 1/16), and Aspergillus sydowi (6.25%, 1/16).
Treatment and prognosis
Treatment of PNTA included general and/or location anti-aspergillus treatment plus interventional therapy by bronchoscope, and the treatment course ranged from 15 days to 12 months. Itraconazole (6 patients), voriconazole (2 patients), amphotericin B liposomes (1 patient), amphotericin B (1 patient) and caspofungin (1 patient) were used for general anti-aspergillus treatment. One patient was treated with itraconazole and caspofungin sequentially, 10 were treated with atomization inhalation amphotericin B injection (12.5 mg) in normal saline (3-5 ml) once daily, eight were treated by direct local perfusion of amphoterincin B (10-15 mg, once or twice each week) by bronchoscope; and five were treated by general and local anti-aspergillus agents (atomization and intralumenal drug perfusion). All 16 patients received interventional treatment by bronchoscope, in which the airway stenosis was relived by removing the necrotic tissue with biopsy forceps and/or resecting the polypoid neoplasm with electric coagulation (1-2 times each week). The treatment cycle was 1-6 months and the follow-up period was 6 months. Three patients (18.8%) were cured, two (12.5%) were effectively treated, two (12.5%) were stable, and nine (56.3%) had progressive disease, with an effective treatment rate of 31.3%. One patient developed hemoptysis asphyxia.
Aspergillus is a widely distributed pathogen and the incidence of infection has been on the rise recently due to the increased number of immunocompromised hosts and improved diagnostic methods.1 Airway aspergillosis is rare, and the specific morbidity remains unknown. Reports have shown that the incidence of airway aspergillosis in recipients of lung transplantation is 3%-22%, and about 5%-10% of the airway aspergillosis cases only involved the airway, not infiltrating the lung parenchyma, while 7%-20% of invasive lung aspergillosis cases can also involve the airways.7, 8 Currently airway aspergillus infections have not been well typed.
The clinical type of airway aspergillus infection mainly depends on the characteristics of bronchoscopy findings.4,5,9–11 There are four types of airway aspergillus infection shown in the literature, including invasive tracheobronchial aspergillosis, ulcerative tracheobronchial aspergillosis, PNTA, and tracheobronchial aspergillosis.3,11–15 PNTA is most common type of aspergillus infection and can pose a severe clinical threat. PNTA mainly involves the trachea, primary bronchus and segmental bronchus, with the main clinical manifestations under bronchoscopy being severe airway obstruction (≥50% diameter of the involved airway obstructed) caused by the pseudomembrane made of necrotic tissues and the aspergillus metabolites, and usually without signs of invasive pulmonary aspergillosis. The diagnosis of airway aspergillus infection is based on the pathological tissue, brush smear, and bronchial fluid obtained by bronchoscopy. Through the culture of tissue and/or bronchial fluid, the type of aspergillus can be determined. A sputum smear and/or culture should not be treated as the main diagnostic evidence of aspergillus infection because of the possibility of contamination.3–6,12,16,17
PNTA is most likely to be found in patients with systemic immunodeficiency and/or patients with local airway damage. Immunodeficiency may result from the following situations; organ transplantation, granulocytopenia and/or use of glucocorticoid, long-term use or large doses of antibiotics, diabetes mellitus, advanced cancer, and chronic primary diseases.12 Our patients had various immunodeficiencies, with pulmonary tumors and pulmonary metastatic tumors accounting for 87.5% of the cases. This is different from the reports in the English language literature, where patients with organ transplantation (such as lung transplantation) were found to have a highest incidence of immunodeficiency.3,13,17 The difference might be due to the disease spectrum in our department and the use of bronchoscopy. Local airway damage is another important cause of aspergillus infection; radiotherapy can lead to local immune damage of the airway and damage to the airway mucosa and small vessels, and aspergillus infection may occur following the accumulation of necrotic substance in the lumens of airway.18 Ten of our patients had received radiotherapy for pulmonary tumors. Kramer et al10 reported that aspergillus infection was most likely to involve the bronchial anastomosis site in lung transplantation patients due to insufficient blood supply. Two advanced COPD patients who had received right lung transplantation had an aspergillus infection at the bronchial anastomosis site. Aspergillus infection disappeared without treatment after the collateral circulation in bronchial anastomosis site formed three months later. Clark et al19 reported that prolonged airway intubation and local airway mucosal dysfunction were also important reasons for the infection. Four of our patients with airway stenosis and one with bronchial papillomas developed the infection after repeated interventional treatment using a bronchoscope; electron coagulation, cryotherapy, and repetitive local debridement. All these observations suggest that systemic immunodeficiency, local mucosal damage, and insufficient blood supply can lead to PNTA.
The most common symptoms of our patients included irritable cough and progressive dyspnea, because PNTA mainly involves trachea, primary bronchus and segmental bronchus. Chest X-ray examination can not identify lesions in the airway and is therefore not helpful. High resolution chest CT is of significance for diagnosis of PNTA, usually showing a thickened tracheobronchial wall, outgrowth in the lumens of airway, airway stenosis, sometimes mucosa obstruction, dilatation of distal bronchi and local atelectasis, even calcification of the airway wall.20 The bronchoscopic findings are the main evidence for diagnosis of PNTA. Based on our experience and previous reports,2,4,9,10,19,21 the characteristics of PNTA under bronchoscope are a grayish white moss-like substance attached to the wall of the trachea and bronchus, rubbery and hard to exfoliate, a greatly narrowed airway4,6 usually involving the large airways.
Diagnosis of PNTA should be based on clinical manifestations, image findings, bronchoscopy, pathological examination and fungal culture and identification, with the latter two being the main factors.22Aspergillus fumigatus is the most common species of PNTA.3,23 The treatment guidelines include controlling the infection and keeping the airway opened. Systemic and local anti-aspergillus agents can be used in combination. Systemic anti-aspergillus agents include the following three types: (1) Polyene antibiotics, amphotericin B is used as the first line drug and has satisfactory efficiency. However, it requires a long treatment cycle and has adverse side-effects, like infusion reaction, renal toxicity, and cardiac toxicity, which limit its application. Amphotericin B liposomes have better biocompatibility and fewer adverse effects. (2) Imidazoles, such as voriconazole and itraconazole. Voriconazole has potent anti-aspergillus effect, with better safety, tolerance, and bioavailability when taken orally. Itraconazole is a second line drug and has satisfactory effects. (3) Pneumocandins, like caspofungin, have a better effect against aspergillus with fewer adverse effects, but it is expensive. Combinations of two drugs can yield a better outcome. Methods of anti-aspergillosis treatment include atomization inhalation of amphotericin B or direct local drug perfusion via a bronchoscope, which can greatly improve the treatment efficiency, while the treatment duration depends on the severity of disease and the clinical response of patients.3,16,24 The average treatment duration in our responsive patients was 3.5 months.
Bronchoscopic debridement is an effective way to keep the airway open, and it is suitable for patients with central airway stenosis and involvement in the main bronchi or above. For patients with rubbery pseudomembranous tissues, systemic and local perfusion of anti-aspergillus agents should be given first; when the tissue becomes soft it can be removed step by step using bronchoscopic biopsy forceps. The manipulation of the bronchoscope should be very careful, since aspergillus infection may penetrate the full thickness of the bronchial wall, including the cartilage and even the blood vessels around the bronchi, making the wall very fragile, which is likely to be damaged by improper manipulation of the bronchoscope, causing rupture of arteries and hemoptysis asphyxia.2,19,21,25 Berlinger et al2 reported that an AIDS patient died of hemoptysis asphyxia during electric coagulation of a granuloma by bronchoscopy. In our study, one patient suffering from thymus cancer had severe trachea stenosis because of the pseudomembrane and granulation hyperplasia in the lumen. Fatal hemoptysis occurred when we performed electric coagulation of the granulation by bronchoscopy. The patient finally died of the asphyxia.
Chest CT examination and 3-dimensional reconstruction of the airway should be done to know the blood supply and structure to fully assess the situation before performing the bronchoscopy. It should be noted that since most patients with PNTA have local damage of the airway, bronchoscopy may aggravate the airway damage and interventional therapy by bronchoscope should only be used when the patients have severe dyspnea.26 When there are risks of asphyxia, caution should be taken.4 Since most cases are complicated by primary disease, surgical treatment is not suitable for PNTA patients.3 Moreover, to actively control the pathogen and improve the systemic immune status of patients, eliminating the risk factors of aspergillus infection is also very important.
The prognosis for PNTA patients is generally poor. The effective rate of treatment in our group was 31.3%. Treatment fails in patients with severe primary diseases, poor immune status and unrecoverable damage to local airways. Satisfactory prognoses can be obtained in patients with normal immune status or with recoverable (slight or moderate) damage to the local airway, such as benign stenosis, recurrent cauterization therapy with bronchoscope.4,22
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