BRIEF COMMUNICATION Bronchomediastinal Fistula Caused by Endobronchial Aspergilloma A. Christine Argento1, Cameron R. Wolfe2, Momen M. Wahidi3, Scott L. Shofer3, and Kamran Mahmood3 1 Interventional Pulmonology, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and 2Division of Infectious Diseases, Department of Medicine, and 3Interventional Pulmonology, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, North Carolina
Abstract Rationale: Endobronchial aspergilloma is a rare condition affecting immunocompromised patients. We present three cases resulting in airway fistulae. Case Presentations: A 68-year-old male with orthotopic heart transplantation presented with fatigue, cough, and dyspnea. A computerized tomography (CT) scan of the chest and bronchoscopy revealed an endobronchial right mainstem mass and airway fistula to the mediastinum. The mass was debrided and biopsy showed Aspergillus fumigatus. He was treated with antifungals and recovered. A 52-year-old male with acquired immunodeficiency syndrome presented with cough, dyspnea, and hypoxemia. Chest CT showed a bronchus intermedius mass and fistula to the mediastinum. Bronchoscopy revealed a necrotic endobronchial mass and pseudomembranes and confirmed the presence of a fistula. The mass was resected bronchoscopically and Aspergillus
fumigatus was isolated. He was treated with antifungals and the fistula healed. A 63-year-old male with chronic lymphoid leukemia was admitted for dyspnea, cough, weakness, and dysphagia. Chest CT and bronchoscopy showed a mass causing obstruction of the subglottic trachea and a fistula to the mediastinum. Biopsy showed Aspergillus fumigatus and he was treated with antifungals. The sinus healed but the patient died of leukemia. Main Results: Risk factors for airway aspergilloma include immune deficiency, mucosal damage, and ischemia. We report airway fistula formation as a complication of this infection, which has not been previously emphasized. Conclusions: Endobronchial aspergillomas may form fistulae to the mediastinum. Aggressive treatment with antifungals and bronchoscopic interventions are required. Keywords: bronchoscopy; interventional pulmonology; aspergilloma
(Received in original form June 10, 2014; accepted in final form November 10, 2014 ) Author Contributions: A.C.A.: conception, data collection, manuscript preparation and editing; C.R.W.: manuscript preparation and editing; M.M.W.: manuscript preparation and editing; S.L.S.: manuscript preparation and editing; K.M.: conception, data collection, manuscript preparation and editing. Correspondence and requests for reprints should be addressed to Christine Argento, M.D., 550 Peachtree Street NE, MOT 6th floor, Atlanta, GA 30363. E-mail: [email protected] Ann Am Thorac Soc Vol 12, No 1, pp 91–95, Jan 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201406-247BC Internet address: www.atsjournals.org
Opportunistic fungal infections, especially Aspergillus, are a common cause of morbidity and mortality in immunocompromised hosts (1) and can present with pneumonia and central airway obstruction (2–4). Endobronchial aspergillosis can be seen in 7–20% of patients with concomitant parenchymal involvement (5–8), although it is rarely seen in isolation. We report our experience with three cases of endobronchial aspergillosis notable for prominent airway-to-mediastinum fistula formation. This case series was approved by the
Institutional Review Board (IRB) of Duke University (Durham, NC) under exempt review status (IRB protocol # Pro00021763).
Case 1 A 68-year-old male following orthotopic heart transplantation for ischemic cardiomyopathy presented with 3 months of fatigue, anorexia, nonproductive cough, and progressive dyspnea on exertion. A computerized tomography (CT) scan of the
Argento, Wolfe, Wahidi, et al.: Bronchomediastinal Fistula
chest showed a large paratracheal mass compressing the trachea (Figure 1A). He underwent bronchoscopy that showed a distal tracheal and right mainstem bronchus endobronchial mass with extrinsic compression and significant airway obstruction (Figure 1B). Rigid bronchoscopy was performed and the mass was biopsied and debrided (Figure 1C). Endobronchial biopsy of the mass and cultures showed Aspergillus fumigatus. He was treated with oral voriconazole, intravenous micafungin, and inhaled amphotericin B. A follow-up CT scan of the 91
BRIEF COMMUNICATION Case 3
Figure 1. (A) Computed tomography (CT) scan of the chest showing large paratracheal mass. (B) Bronchoscopic view showing distal tracheal/right mainstem bronchus mass (arrow). (C) Bronchoscopic view: Distal tracheal/right mainstem bronchus mass after debridement. (D) CT chest (1 mo later) with fistula originating from distal trachea (arrow). (E ) Bronchoscopic view: Fistula originating from distal trachea (arrow).
chest 1 month later revealed a tracheal fistula leading into the mediastinum and bilateral pleural effusions (Figure 1D). Follow-up bronchoscopy showed significant resolution of the endobronchial mass; however, a tracheomediastinal fistula was now visible (Figure 1E). The patient was treated with the combination of antifungals described previously for a total of 5 weeks and he is alive 11 months after the initial diagnosis, continued on suppressive therapy with voriconazole.
Case 2 A 52-year-old male with acquired immunodeficiency syndrome (AIDS) presented with several months of persistent cough, dyspnea on exertion, and hypoxemia. A CT scan of the chest showed wall thickening and stenosis of the right mainstem and bronchus intermedius with 92
a fistula leading to the mediastinum (Figure 2A). Tree-in-bud opacities were seen in the right middle and lower lobes consistent with pneumonia. Bronchoscopy revealed a necrotic mass and pseudomembranes at the main carina extending into the right mainstem and bronchus intermedius (Figure 2B). He underwent rigid bronchoscopy for debridement of the mass and pseudomembranes (Figures 2C and 2D). The endobronchial biopsies showed necrotic tissue laden with Aspergillus fumigatus. He was treated with oral voriconazole and intravenous micafungin for 2 months followed by chronic maintenance therapy with voriconazole. The fistula healed, but he developed progressive stenosis of the bronchus intermedius (Figure 2E) that required multiple dilations and eventually an endobronchial stent placement (Figure 2F). The patient is alive 30 months after his initial presentation and is doing well.
A 63-year-old male with chronic lymphoid leukemia (CLL) presented with progressive dyspnea, cough productive of white sputum, weakness, and dysphagia. A CT scan of his chest showed soft tissue infiltration with narrowing of the subglottic trachea; free air in the superior mediastinum; and bilateral, diffuse groundglass and nodular infiltrates (Figure 3A). Bronchoscopy revealed an endobronchial mass causing more than 50% obstruction of the subglottic trachea and a fistulous tract expressing purulent material leading to the mediastinum (Figure 3B). He then underwent debridement with rigid bronchoscopy (Figure 3C) and endobronchial biopsy cultures grew Aspergillus fumigatus. He was treated with oral voriconazole, intravenous micafungin, and inhaled amphotericin B for 3 months. He also grew mixed anaerobic grampositive and gram-negative organisms on the tissue culture and was treated for 14 days with intravenous vancomycin and piperacillin/tazobactam. He underwent two subsequent bronchoscopic debridements for airway clearance and the fistula healed (Figure 3D). However, the patient died 3 months after the initial diagnosis secondary to progression of leukemia.
Discussion Aspergillus is a filamentous fungus that is ubiquitous in the environment, found in the soil, water, and on organic debris (2, 3). Aspergillus species are the most common cause of mortality due to invasive mycoses in the United States (9). More than 300 species of Aspergillus have been identified, although only 19 species have been described to cause disease in humans. The most common pathogenic species are Aspergillus fumigatus, Aspergillus niger, and Aspergillus flavus (5). Pathogenesis involves the production of endotoxins and proteases such as elastase, collagenase, and trypsin that damage the epithelium, leading to a high rate of angioinvasion in the immunocompromised host. Impairment of a patient’s local and systemic immune system, particularly neutropenia and loss of tissue macrophages, predispose to Aspergillus
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Figure 2. (A) Computed tomography (CT) scan of the chest with fistula from the bronchus intermedius. (B) Bronchus intermedius completely obstructed with endobronchial mass and pseudomembranes. (C) Bronchus intermedius after debridement. (D) Bronchus intermedius fistula after debulking. (E ) Chronic stenosis of bronchus intermedius on follow-up bronchoscopy. (F ) Bronchus intermedius after stent placement.
infection (2, 3, 5). Other risk factors include surgical instrumentation and radiation therapy, which can cause disruption of mucociliary clearance, impaired lymphatic drainage, and ischemia. Aspergillus infection of the airway usually accompanies invasive aspergillosis involving the lung parenchyma. However, 5–10% of the cases of airway aspergillosis can be seen without the invasive parenchymal disease (2, 3, 6). Presenting signs and symptoms are nonspecific and include cough, dyspnea, hemoptysis, and chest pain. Signs or symptoms of sepsis may notably be absent in the immunocompromised host (3). Endobronchial aspergillosis is a poor prognostic sign, and reported mortality up to 48% has been described (3). Radiographically, a chest roentgenogram (CXR) often shows multiple nodular opacities with irregular margins, peripheral wedge-shaped opacities corresponding to infarcts, or an air-crescent sign correlating with lung
necrosis. The CXR can also appear normal with infection that is limited to the tracheobronchial tree (10). A chest CT scan can demonstrate consolidation, infarction, or nodules with or without the halo sign. When the disease is limited to the airways, tracheal or bronchial wall thickening or an endobronchial mass with or without lobar or segmental atelectasis can be seen. Bronchoscopic findings include endobronchial masses, pseudomembranes, mucosal surface ulcerations, and purulent exudates (3, 6). Fistulae are rare. In lung transplant recipients, Aspergillus is reported to erode from the airway into the mediastinum (1), esophagus (11), or vasculature (12–14), especially from the anastomosis site. The anastomosis represents an area of significant mucosal disruption, which combined with ischemia from the sutures and loss of bronchial circulation as well as immunosuppressive agents presents an optimal environment for Aspergillus to erode into the surrounding structures (3).
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Bronchopleural fistulas can arise from rupture of an aspergilloma cavity into the pleural space or from direct infection arising from the pleura. The treatment for these patients is mostly surgical with or without local and systemic antifungal therapy (15–17). Interestingly, these bronchopleural fistulas have also been described to extend and form pleuroperitoneal (18) or pleurocutaneous (16) fistulas if not treated in a timely fashion. A bronchoesophageal fistula has been described and was diagnosed after a patient expectorated an Aspergillus mycetoma that had been known to affect the lungs (19). Bronchovascular fistulas are fairly well described secondary to infection with Aspergillus. These fistulas can form a communication of the tracheobronchial tree to the aorta (20), the pulmonary artery (21–25), or even to the pericardium (26, 27). These fistulae are often fatal and present with massive hemoptysis. The treatment goal is to control the bleeding, which is most commonly achieved surgically, although endovascular and endoscopic/bronchoscopic interventions can be successful such as stenting and coiling to stabilize the patient before surgery. Once interventions are completed, a prolonged course (weeks) of antifungal therapy is recommended and can be a combination of systemic, aerosolized, and local agents (24). Bronchial– pulmonary artery fistulae are more commonly described in lung transplant patients as the pulmonary arteries run in close proximity to the anastomosis sites bilaterally. Bronchocardiac and bronchomediastinal (10) fistulas have been reported in neutropenic and granulocytopenic patients such as organ transplant recipients, those with advanced acquired immunodeficiency syndrome (AIDS), diabetics, and patients receiving prolonged corticosteroid therapy. In these patients, necrotizing pneumonia or mediastinitis can cause a fistula to develop to the pericardium, which can lead to hemorrhage, tamponade, and air embolism. Treatment options described in the literature for bronchopleural fistulae include systemic, inhaled, or aerosolized antifungals and local therapy with transbronchial or topical administration of liposomal amphotericin B (24, 28). 93
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Figure 3. (A) Computed tomography (CT) scan showing subglottic stenosis and mediastinal air. (B) Subglottic mass causing significant stenosis. (C) Subglottic mass after debridement revealed a fistula (arrow). (D) Fistula and subglottic mass resolved.
Local therapy is thought to accomplish a targeted sclerosis of the cavity and assist with its resolution (29). Also described are muscle flaps over airway anastomoses or surgical stumps to assist with revascularization and thereby lessen ischemia. These flaps are often combined with sealants such as fibrin glue, which help to close the fistula and promote healing (30–32). There is also a report of neodymium:yttrium–aluminum garnet laser therapy to help close
a bronchopleural fistula at a surgical stump. Laser therapy caused edema and granulation tissue formation that closed the fistula. Of note, this treatment modality was not effective when the tissue was infected with Aspergillus (33). Finally, video-assisted thoracoscopic surgery can be used to irrigate the chest as well as to localize and either apply a fibrin sealant or surgically remove the area affected by infection and fistula (34).
Our series is unique because all the patients developed fistulae from the endobronchial aspergilloma into the mediastinum, yet none had prior surgical disruption. Chest CT scan and bronchoscopy revealed the fistula. Tracheoesophageal fistulae have been described in patients with invasive aspergillosis (10). To our knowledge, there is only scant literature about bronchomediastinal fistula secondary to airway aspergillosis (10, 24, 35). Our patients were treated with a combination of multiple systemic and inhaled antifungals (Table 1). Although there are no large studies to provide data that support combination therapy, the American Thoracic Society and the Infectious Diseases Society of America recommend that individual cases be treated with multiple antifungal medications if their immune suppression cannot be reversed or reduced and they present with moderate to severe aspergillosis (9, 36). Duration of treatment is typically 6–12 weeks or as otherwise dictated by clinical response. In our series, clinical response was assessed by repeat chest CT scans and bronchoscopy to ensure resolution of the endobronchial mass and fistulae. Surveillance cultures may also be obtained to document remission. A prophylactic regimen may be required indefinitely if immune suppression cannot be reversed. Our case series also highlights the important role of therapeutic
Table 1. Summary of patients with endobronchial aspergilloma Patient
Underlying Immune Deficiency
1
OHT
2
AIDS
3
CLL
Radiographic Findings
Bronchoscopic Findings
Treatments
Follow-Up
Distal tracheal fistula leading into the mediastinum
Endobronchial mass in Rigid bronchoscopic Healed fistula and distal trachea and RMS, debridement. resolution of the and airway fistula from Voriconazole, aspergilloma distal trachea to the micafungin, mediastinum amphotericin B (inhaled) Airway thickening and RMS/BI mass, Rigid bronchoscopic Healed fistula. BI stenosis stenosis of RMS/BI. pseudomembranes and debridement. requiring multiple Airway fistula from the stenosis with fistula Voriconazole, dilations and stent BI leading into the from BI into the micafungin placement mediastinum mediastinum Soft tissue infiltration and Subglottic mass and Rigid bronchoscopic Healed tracheal fistula narrowing of subglottic stenosis with fistula debridement. trachea with several from trachea leading Voriconazole, pockets of free air in the into the mediastinum micafungin, mediastinum amphotericin B (inhaled)
Definition of abbreviations: AIDS = acquired immunodeficiency syndrome; BI = bronchus intermedius; CLL = chronic lymphoid leukemia; OHT = orthotopic heart transplant; RMS = right mainstem.
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BRIEF COMMUNICATION bronchoscopy to resect endobronchial aspergillomas, especially in patients presenting with central airway obstruction. One patient developed airway stenosis from scar tissue that
required multiple dilations and eventually endobronchial stent placement. Despite historically poor outcomes, our series demonstrates that with combination antifungal therapy and therapeutic
References 1 Mehrad B, Paciocco G, Martinez FJ, Ojo TC, Iannettoni MD, Lynch JP III. Spectrum of Aspergillus infection in lung transplant recipients: case series and review of the literature. Chest 2001;119:169–175. 2 Al-Alawi A, Ryan CF, Flint JD, Muller ¨ NL. Aspergillus-related lung disease. Can Respir J 2005;12:377–387. 3 Karnak D, Avery RK, Gildea TR, Sahoo D, Mehta AC. Endobronchial fungal disease: an under-recognized entity. Respiration 2007;74: 88–104. 4 Kemper CA, Hostetler JS, Follansbee SE, Ruane P, Covington D, Leong SS, Deresinski SC, Stevens DA. Ulcerative and plaque-like tracheobronchitis due to infection with Aspergillus in patients with AIDS. Clin Infect Dis 1993;17:344–352. 5 Bardana EJ Jr. The clinical spectrum of aspergillosis—part 1: epidemiology, pathogenicity, infection in animals and immunology of Aspergillus. Crit Rev Clin Lab Sci 1981;13:21–83. 6 Huang HD, Li Q, Huang Y, Bai C, Wu N, Wang Q, Yao XP, Chen B. Pseudomembranous necrotizing tracheobronchial aspergillosis: an analysis of 16 cases. Chin Med J (Engl) 2012;125:1236–1241. 7 Limper AH. The changing spectrum of fungal infections in pulmonary and critical care practice: clinical approach to diagnosis. Proc Am Thorac Soc 2010;7:163–168. 8 Xu H, Li L, Huang WJ, Wang LX, Li WF, Yuan WF. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: a case control study from China. Clin Microbiol Infect 2012;18: 403–408. 9 Limper AH, Knox KS, Sarosi GA, Ampel NM, Bennett JE, Catanzaro A, Davies SF, Dismukes WE, Hage CA, Marr KA, et al.; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96–128. 10 Vail CM, Chiles C. Invasive pulmonary aspergillosis: radiologic evidence of tracheal involvement. Radiology 1987;165:745–746. 11 Stack BC Jr, Ridley MB, Greene JN, Hubbell DS. Tracheoesophageal fistula and sinusitis from invasive aspergillosis. Otolaryngol Head Neck Surg 1997;116:116–119. 12 Kessler R, Massard G, Warter A, Wihlm JM, Weitzenblum E. Bronchial– pulmonary artery fistula after unilateral lung transplantation: a case report. J Heart Lung Transplant 1997;16:674–677. 13 Knight J, Elwing JM, Milstone A. Bronchovascular fistula formation: a rare airway complication after lung transplantation. J Heart Lung Transplant 2008;27:1179–1185. 14 van de Graaf EA, Kwakkel-van Erp JM, van Kessel DA, van den Bosch JM, van Oosterhout MF, Vink A. Bronchovascular fistula formation after lung transplantation. J Heart Lung Transplant 2009;28:531–532. 15 Hillerdal G. Pulmonary Aspergillus infection invading the pleura. Thorax 1981;36:745–751. 16 Soto-Hurtado EJ, Mar´ın-Gamez ´ E, Segura-Dom´ınguez N, Jimenez´ Oñate F. Pleural aspergillosis with bronchopleurocutaneous fistula and costal bone destruction: a case report. Lung 2005;183:417–423. 17 Herer B, Assier-Bonnet H, Zalcman G, Roig C, Hirsch A. [Peritoneal fistulization in pleural aspergillosis associated with skin lesions] [article in French]. Rev Mal Respir 1999;16:1157–1159. 18 Ko SC, Chen KY, Hsueh PR, Luh KT, Yang PC. Fungal empyema thoracis: an emerging clinical entity. Chest 2000;117:1672–1678. 19 Mineur P, Ferrant A, Wallon J, Otte JB, Michaux JL. Bronchoesophageal fistula caused by pulmonary aspergillosis. Eur J Respir Dis 1985;66:360–366.
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bronchoscopic resection, excellent outcomes can be achieved. n Author disclosures are available with the text of this article at www.atsjournals.org.
20 Islam S, Williams DM, Teitelbaum DH. Aortobronchial fistula from invasive Aspergillus infection of the lung: an endovascular approach to repair. J Pediatr Surg 2005;40:e19–e22. 21 Guth S, Mayer E, Fischer B, Lill J, Weiler N, Oelert H. Bilobectomy for massive hemoptysis after bilateral lung transplantation. J Thorac Cardiovasc Surg 2001;121:1194–1195. 22 Pinet C, Palka W, Metras D, Thomas P, Meric ´ B, Dumon JF. Management of an intrabronchial rupture of right main pulmonary artery: a case report. Chest 2002;121:988–990. 23 Slatore CG, Yank V, Jewell KD, Fligner CL. Bronchial–pulmonary artery fistula with fatal massive hemoptysis caused by anastomotic bronchial Aspergillus infection in a lung transplant recipient. Respir Care 2007;52:1542–1545. 24 Boettcher H, Bewig B, Hirt SW, Moller ¨ F, Cremer J. Topical amphotericin B application in severe bronchial aspergillosis after lung transplantation: report of experiences in 3 cases. J Heart Lung Transplant 2000;19:1224–1227. 25 Rea F, Marulli G, Loy M, Bortolotti L, Giacometti C, Schiavon M, Calabrese F. Salvage right pneumonectomy in a patient with bronchial–pulmonary artery fistula after bilateral sequential lung transplantation. J Heart Lung Transplant 2006;25:1383–1386. 26 Le Moing V, Lortholary O, Timsit JF, Couvelard A, Bouges-Michel C, Wolff M, Guillevin L, Casassus P. Aspergillus pericarditis with tamponade: report of a successfully treated case and review. Clin Infect Dis 1998;26:451–460. 27 van Ede AE, Meis JF, Koot RA, Heystraten FM, de Pauw BE. Pneumopericardium complicating invasive pulmonary aspergillosis: case report and review. Infection 1994;22:102–105. 28 Baquero-Artigao F, Garc´ıa-Miguel MJ, Hernandez ´ F, Hernandez ´ N, del Castillo F. Combined systemic and intrapleural treatment of Aspergillus pulmonary empyema after invasive aspergillosis. Pediatr Infect Dis J 2003;22:471–473. 29 Takeda T, Itano H, Ryouhei K, Fukita S, Saitoh M, Takeda S. Direct transbronchial administration of liposomal amphotericin B into a pulmonary aspergilloma. Respir Med Case Rep 2014;11:7–11. 30 Keckler SJ, Spilde TL, St Peter SD, Tsao K, Ostlie DJ. Treatment of bronchopleural fistula with small intestinal mucosa and fibrin glue sealant. Ann Thorac Surg 2007;84:1383–1386. 31 Taghavi S, Marta GM, Lang G, Seebacher G, Winkler G, Schmid K, Klepetko W. Bronchial stump coverage with a pedicled pericardial flap: an effective method for prevention of postpneumonectomy bronchopleural fistula. Ann Thorac Surg 2005;79:284–288. 32 Baumann WR, Ulmer JL, Ambrose PG, Garvey MJ, Jones DT. Closure of a bronchopleural fistula using decalcified human spongiosa and a fibrin sealant. Ann Thorac Surg 1997;64:230–233. 33 Kiriyama M, Fujii Y, Yamakawa Y, Fukai I, Yano M, Kaji M, Sasaki H. Endobronchial neodymium:yttrium-aluminum garnet laser for noninvasive closure of small proximal bronchopleural fistula after lung resection. Ann Thorac Surg 2002;73:945–948, discussion 948– 949. 34 Feng Q, Ma L, Gabrielle G, Yu GW. Use of video-assisted thoracoscopy surgery for the treatment of Aspergillus empyema with bronchopleural fistula. Thorac Cardiovasc Surg 2008;56:370–372. 35 Drury AE, Allan RA, Underhill H, Ball S, Joseph AE. Calcification in invasive tracheal aspergillosis demonstrated on ultrasound: a new finding. Br J Radiol 2001;74:955–958. 36 Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, et al.; Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46:327–360.
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Abstract Rationale: Endobronchial aspergilloma is a rare condition affecting immunocompromised patients. We present three cases resulting in airway fistulae. Case Presentations: A 68-year-old male with orthotopic heart transplantation presented with fatigue, cough, and dyspnea. A computerized tomography (CT) scan of the chest and bronchoscopy revealed an endobronchial right mainstem mass and airway fistula to the mediastinum. The mass was debrided and biopsy showed Aspergillus fumigatus. He was treated with antifungals and recovered. A 52-year-old male with acquired immunodeficiency syndrome presented with cough, dyspnea, and hypoxemia. Chest CT showed a bronchus intermedius mass and fistula to the mediastinum. Bronchoscopy revealed a necrotic endobronchial mass and pseudomembranes and confirmed the presence of a fistula. The mass was resected bronchoscopically and Aspergillus
fumigatus was isolated. He was treated with antifungals and the fistula healed. A 63-year-old male with chronic lymphoid leukemia was admitted for dyspnea, cough, weakness, and dysphagia. Chest CT and bronchoscopy showed a mass causing obstruction of the subglottic trachea and a fistula to the mediastinum. Biopsy showed Aspergillus fumigatus and he was treated with antifungals. The sinus healed but the patient died of leukemia. Main Results: Risk factors for airway aspergilloma include immune deficiency, mucosal damage, and ischemia. We report airway fistula formation as a complication of this infection, which has not been previously emphasized. Conclusions: Endobronchial aspergillomas may form fistulae to the mediastinum. Aggressive treatment with antifungals and bronchoscopic interventions are required. Keywords: bronchoscopy; interventional pulmonology; aspergilloma
(Received in original form June 10, 2014; accepted in final form November 10, 2014 ) Author Contributions: A.C.A.: conception, data collection, manuscript preparation and editing; C.R.W.: manuscript preparation and editing; M.M.W.: manuscript preparation and editing; S.L.S.: manuscript preparation and editing; K.M.: conception, data collection, manuscript preparation and editing. Correspondence and requests for reprints should be addressed to Christine Argento, M.D., 550 Peachtree Street NE, MOT 6th floor, Atlanta, GA 30363. E-mail: [email protected] Ann Am Thorac Soc Vol 12, No 1, pp 91–95, Jan 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201406-247BC Internet address: www.atsjournals.org
Opportunistic fungal infections, especially Aspergillus, are a common cause of morbidity and mortality in immunocompromised hosts (1) and can present with pneumonia and central airway obstruction (2–4). Endobronchial aspergillosis can be seen in 7–20% of patients with concomitant parenchymal involvement (5–8), although it is rarely seen in isolation. We report our experience with three cases of endobronchial aspergillosis notable for prominent airway-to-mediastinum fistula formation. This case series was approved by the
Institutional Review Board (IRB) of Duke University (Durham, NC) under exempt review status (IRB protocol # Pro00021763).
Case 1 A 68-year-old male following orthotopic heart transplantation for ischemic cardiomyopathy presented with 3 months of fatigue, anorexia, nonproductive cough, and progressive dyspnea on exertion. A computerized tomography (CT) scan of the
Argento, Wolfe, Wahidi, et al.: Bronchomediastinal Fistula
chest showed a large paratracheal mass compressing the trachea (Figure 1A). He underwent bronchoscopy that showed a distal tracheal and right mainstem bronchus endobronchial mass with extrinsic compression and significant airway obstruction (Figure 1B). Rigid bronchoscopy was performed and the mass was biopsied and debrided (Figure 1C). Endobronchial biopsy of the mass and cultures showed Aspergillus fumigatus. He was treated with oral voriconazole, intravenous micafungin, and inhaled amphotericin B. A follow-up CT scan of the 91
BRIEF COMMUNICATION Case 3
Figure 1. (A) Computed tomography (CT) scan of the chest showing large paratracheal mass. (B) Bronchoscopic view showing distal tracheal/right mainstem bronchus mass (arrow). (C) Bronchoscopic view: Distal tracheal/right mainstem bronchus mass after debridement. (D) CT chest (1 mo later) with fistula originating from distal trachea (arrow). (E ) Bronchoscopic view: Fistula originating from distal trachea (arrow).
chest 1 month later revealed a tracheal fistula leading into the mediastinum and bilateral pleural effusions (Figure 1D). Follow-up bronchoscopy showed significant resolution of the endobronchial mass; however, a tracheomediastinal fistula was now visible (Figure 1E). The patient was treated with the combination of antifungals described previously for a total of 5 weeks and he is alive 11 months after the initial diagnosis, continued on suppressive therapy with voriconazole.
Case 2 A 52-year-old male with acquired immunodeficiency syndrome (AIDS) presented with several months of persistent cough, dyspnea on exertion, and hypoxemia. A CT scan of the chest showed wall thickening and stenosis of the right mainstem and bronchus intermedius with 92
a fistula leading to the mediastinum (Figure 2A). Tree-in-bud opacities were seen in the right middle and lower lobes consistent with pneumonia. Bronchoscopy revealed a necrotic mass and pseudomembranes at the main carina extending into the right mainstem and bronchus intermedius (Figure 2B). He underwent rigid bronchoscopy for debridement of the mass and pseudomembranes (Figures 2C and 2D). The endobronchial biopsies showed necrotic tissue laden with Aspergillus fumigatus. He was treated with oral voriconazole and intravenous micafungin for 2 months followed by chronic maintenance therapy with voriconazole. The fistula healed, but he developed progressive stenosis of the bronchus intermedius (Figure 2E) that required multiple dilations and eventually an endobronchial stent placement (Figure 2F). The patient is alive 30 months after his initial presentation and is doing well.
A 63-year-old male with chronic lymphoid leukemia (CLL) presented with progressive dyspnea, cough productive of white sputum, weakness, and dysphagia. A CT scan of his chest showed soft tissue infiltration with narrowing of the subglottic trachea; free air in the superior mediastinum; and bilateral, diffuse groundglass and nodular infiltrates (Figure 3A). Bronchoscopy revealed an endobronchial mass causing more than 50% obstruction of the subglottic trachea and a fistulous tract expressing purulent material leading to the mediastinum (Figure 3B). He then underwent debridement with rigid bronchoscopy (Figure 3C) and endobronchial biopsy cultures grew Aspergillus fumigatus. He was treated with oral voriconazole, intravenous micafungin, and inhaled amphotericin B for 3 months. He also grew mixed anaerobic grampositive and gram-negative organisms on the tissue culture and was treated for 14 days with intravenous vancomycin and piperacillin/tazobactam. He underwent two subsequent bronchoscopic debridements for airway clearance and the fistula healed (Figure 3D). However, the patient died 3 months after the initial diagnosis secondary to progression of leukemia.
Discussion Aspergillus is a filamentous fungus that is ubiquitous in the environment, found in the soil, water, and on organic debris (2, 3). Aspergillus species are the most common cause of mortality due to invasive mycoses in the United States (9). More than 300 species of Aspergillus have been identified, although only 19 species have been described to cause disease in humans. The most common pathogenic species are Aspergillus fumigatus, Aspergillus niger, and Aspergillus flavus (5). Pathogenesis involves the production of endotoxins and proteases such as elastase, collagenase, and trypsin that damage the epithelium, leading to a high rate of angioinvasion in the immunocompromised host. Impairment of a patient’s local and systemic immune system, particularly neutropenia and loss of tissue macrophages, predispose to Aspergillus
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Figure 2. (A) Computed tomography (CT) scan of the chest with fistula from the bronchus intermedius. (B) Bronchus intermedius completely obstructed with endobronchial mass and pseudomembranes. (C) Bronchus intermedius after debridement. (D) Bronchus intermedius fistula after debulking. (E ) Chronic stenosis of bronchus intermedius on follow-up bronchoscopy. (F ) Bronchus intermedius after stent placement.
infection (2, 3, 5). Other risk factors include surgical instrumentation and radiation therapy, which can cause disruption of mucociliary clearance, impaired lymphatic drainage, and ischemia. Aspergillus infection of the airway usually accompanies invasive aspergillosis involving the lung parenchyma. However, 5–10% of the cases of airway aspergillosis can be seen without the invasive parenchymal disease (2, 3, 6). Presenting signs and symptoms are nonspecific and include cough, dyspnea, hemoptysis, and chest pain. Signs or symptoms of sepsis may notably be absent in the immunocompromised host (3). Endobronchial aspergillosis is a poor prognostic sign, and reported mortality up to 48% has been described (3). Radiographically, a chest roentgenogram (CXR) often shows multiple nodular opacities with irregular margins, peripheral wedge-shaped opacities corresponding to infarcts, or an air-crescent sign correlating with lung
necrosis. The CXR can also appear normal with infection that is limited to the tracheobronchial tree (10). A chest CT scan can demonstrate consolidation, infarction, or nodules with or without the halo sign. When the disease is limited to the airways, tracheal or bronchial wall thickening or an endobronchial mass with or without lobar or segmental atelectasis can be seen. Bronchoscopic findings include endobronchial masses, pseudomembranes, mucosal surface ulcerations, and purulent exudates (3, 6). Fistulae are rare. In lung transplant recipients, Aspergillus is reported to erode from the airway into the mediastinum (1), esophagus (11), or vasculature (12–14), especially from the anastomosis site. The anastomosis represents an area of significant mucosal disruption, which combined with ischemia from the sutures and loss of bronchial circulation as well as immunosuppressive agents presents an optimal environment for Aspergillus to erode into the surrounding structures (3).
Argento, Wolfe, Wahidi, et al.: Bronchomediastinal Fistula
Bronchopleural fistulas can arise from rupture of an aspergilloma cavity into the pleural space or from direct infection arising from the pleura. The treatment for these patients is mostly surgical with or without local and systemic antifungal therapy (15–17). Interestingly, these bronchopleural fistulas have also been described to extend and form pleuroperitoneal (18) or pleurocutaneous (16) fistulas if not treated in a timely fashion. A bronchoesophageal fistula has been described and was diagnosed after a patient expectorated an Aspergillus mycetoma that had been known to affect the lungs (19). Bronchovascular fistulas are fairly well described secondary to infection with Aspergillus. These fistulas can form a communication of the tracheobronchial tree to the aorta (20), the pulmonary artery (21–25), or even to the pericardium (26, 27). These fistulae are often fatal and present with massive hemoptysis. The treatment goal is to control the bleeding, which is most commonly achieved surgically, although endovascular and endoscopic/bronchoscopic interventions can be successful such as stenting and coiling to stabilize the patient before surgery. Once interventions are completed, a prolonged course (weeks) of antifungal therapy is recommended and can be a combination of systemic, aerosolized, and local agents (24). Bronchial– pulmonary artery fistulae are more commonly described in lung transplant patients as the pulmonary arteries run in close proximity to the anastomosis sites bilaterally. Bronchocardiac and bronchomediastinal (10) fistulas have been reported in neutropenic and granulocytopenic patients such as organ transplant recipients, those with advanced acquired immunodeficiency syndrome (AIDS), diabetics, and patients receiving prolonged corticosteroid therapy. In these patients, necrotizing pneumonia or mediastinitis can cause a fistula to develop to the pericardium, which can lead to hemorrhage, tamponade, and air embolism. Treatment options described in the literature for bronchopleural fistulae include systemic, inhaled, or aerosolized antifungals and local therapy with transbronchial or topical administration of liposomal amphotericin B (24, 28). 93
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Figure 3. (A) Computed tomography (CT) scan showing subglottic stenosis and mediastinal air. (B) Subglottic mass causing significant stenosis. (C) Subglottic mass after debridement revealed a fistula (arrow). (D) Fistula and subglottic mass resolved.
Local therapy is thought to accomplish a targeted sclerosis of the cavity and assist with its resolution (29). Also described are muscle flaps over airway anastomoses or surgical stumps to assist with revascularization and thereby lessen ischemia. These flaps are often combined with sealants such as fibrin glue, which help to close the fistula and promote healing (30–32). There is also a report of neodymium:yttrium–aluminum garnet laser therapy to help close
a bronchopleural fistula at a surgical stump. Laser therapy caused edema and granulation tissue formation that closed the fistula. Of note, this treatment modality was not effective when the tissue was infected with Aspergillus (33). Finally, video-assisted thoracoscopic surgery can be used to irrigate the chest as well as to localize and either apply a fibrin sealant or surgically remove the area affected by infection and fistula (34).
Our series is unique because all the patients developed fistulae from the endobronchial aspergilloma into the mediastinum, yet none had prior surgical disruption. Chest CT scan and bronchoscopy revealed the fistula. Tracheoesophageal fistulae have been described in patients with invasive aspergillosis (10). To our knowledge, there is only scant literature about bronchomediastinal fistula secondary to airway aspergillosis (10, 24, 35). Our patients were treated with a combination of multiple systemic and inhaled antifungals (Table 1). Although there are no large studies to provide data that support combination therapy, the American Thoracic Society and the Infectious Diseases Society of America recommend that individual cases be treated with multiple antifungal medications if their immune suppression cannot be reversed or reduced and they present with moderate to severe aspergillosis (9, 36). Duration of treatment is typically 6–12 weeks or as otherwise dictated by clinical response. In our series, clinical response was assessed by repeat chest CT scans and bronchoscopy to ensure resolution of the endobronchial mass and fistulae. Surveillance cultures may also be obtained to document remission. A prophylactic regimen may be required indefinitely if immune suppression cannot be reversed. Our case series also highlights the important role of therapeutic
Table 1. Summary of patients with endobronchial aspergilloma Patient
Underlying Immune Deficiency
1
OHT
2
AIDS
3
CLL
Radiographic Findings
Bronchoscopic Findings
Treatments
Follow-Up
Distal tracheal fistula leading into the mediastinum
Endobronchial mass in Rigid bronchoscopic Healed fistula and distal trachea and RMS, debridement. resolution of the and airway fistula from Voriconazole, aspergilloma distal trachea to the micafungin, mediastinum amphotericin B (inhaled) Airway thickening and RMS/BI mass, Rigid bronchoscopic Healed fistula. BI stenosis stenosis of RMS/BI. pseudomembranes and debridement. requiring multiple Airway fistula from the stenosis with fistula Voriconazole, dilations and stent BI leading into the from BI into the micafungin placement mediastinum mediastinum Soft tissue infiltration and Subglottic mass and Rigid bronchoscopic Healed tracheal fistula narrowing of subglottic stenosis with fistula debridement. trachea with several from trachea leading Voriconazole, pockets of free air in the into the mediastinum micafungin, mediastinum amphotericin B (inhaled)
Definition of abbreviations: AIDS = acquired immunodeficiency syndrome; BI = bronchus intermedius; CLL = chronic lymphoid leukemia; OHT = orthotopic heart transplant; RMS = right mainstem.
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required multiple dilations and eventually endobronchial stent placement. Despite historically poor outcomes, our series demonstrates that with combination antifungal therapy and therapeutic
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