Mediastinal Mass Due to Aspergillus fumigatus After Lung Transplantation: A Case Report Oksana Anatolia Shlobin, MD,a Lesia K. Dropulic, MDb Jonathan B. Orens, MD,a John F. Mcdyer, MD,a John V. Conte, MD,c Stephen Y. Yang, MD,c and Reda Girgis, MDa We report a rare case of mediastinal mass caused by Aspergillus fumigatus in a lung transplant recipient. The patient presented 9 months after bilateral lung transplantation for cystic fibrosis with intermittent fevers and new onset atrial fibrillation/flutter caused by a 7-cm mediastinal mass invading the left atrium. The mass was resected, and a prolonged course of voriconazole and caspofungin was given, which resulted in a complete clinical response. Despite long-term suppressive therapy with voriconazole, a relapse occurred 16 months after the initial diagnosis. This case highlights the challenges in the prevention and treatment of invasive aspergillosis in lung transplant recipients. J Heart Lung Transplant 2005;24:1991– 4. Copyright © 2005 by the International Society for Heart and Lung Transplantation.
Infections are the most common cause of early death after lung transplantation. Bacterial organisms cause most infections, but viruses (cytomegalovirus, herpes simplex virus, influenza) and fungi (Aspergillus, Candida, Pneumocystis carinii pneumonia) also contribute significantly to mortality and morbidity.1 Aspergillus colonization is common in lung transplant recipients. Although invasive infections are infrequent, occurring in 6% to 10% of patients in various series, they carry a 73% mortality rate.2– 4 Most documented invasive infections involve the lungs, but mediastinal invasion has not been reported. In this report present an unusual case of a mediastinal mass and subsequent cardiac mass caused by Aspergillus fumigatus to emphasize the need to include this infection in the differential diagnosis of mediastinal abnormalities after lung transplantation. CASE REPORT Nine months after a bilateral lung transplantation for cystic fibrosis, a 30-year-old woman was admitted to the hospital with new onset of atrial flutter/fibrillation that required cardioversion and treatment with amiodarone and warfarin. The following month, she presented with complaints of intermittent fever to 38° C for several weeks without any associated symptoms. The patient’s
From the Departments of aPulmonary and Critical Care Medicine, b Infectious Diseases, and c Thoracic Surgery, Johns Hopkins Medical Institutes, Baltimore, Maryland. Submitted November 15, 2004; revised February 14, 2005; accepted February 17, 2005. Reprint requests: Oksana A. Shlobin, MD, Johns Hopkins Medical Institutes, Pulmonary/Critical Care Medicine, 1830 East Monument Street, 5th Floor, Baltimore, Maryland 21230. Telephone: 410-9553457. Fax: 410-955-0036. E-mail:
[email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2005.02.020
immunosuppressive regimen consisted of tacrolimus, prednisone, and azathioprine. She had received prophylactic trimethoprim/sulfamethoxazole, acyclovir, and itraconazole for prophylaxis from the time of transplantation until her illness. The physical exam, remarkable for low-grade fever, was otherwise normal. The results of all the laboratory studies were within normal limits. Cytomegalovirus (CMV) antigenemia and several sets of bacterial, fungal, and CMV blood cultures were negative, as were urine and stool cultures. Pre-transplant sputum analysis revealed colonization with Aspergillus fumigatus and Alcaligenes xylosoxidans. The patient’s pre-transplant CMV immunoglobulin (IgG) was negative, and the donor was CMV IgG positive (D⫹/R⫺). Post-transplant, CMV hyperimmune globulin and 90 days of intravenous (IV) ganciclovir were given. The most recent post-transplant surveillance bronchioalveolar lavage (BAL) cultures performed before presentation grew Alcaligenes xylosoxidans and Stenotrophomonas maltophilia. Aspergillus species never grew from her surveillance bronchoscopies performed at 1, 3, and 6 months after transplant. Chest X-ray showed no parenchymal infiltrates, but slight splaying of the carina was present. Non-contrast chest computed tomography (CT) suggested a subcarinal mediastinal mass. Chest magnetic resonance imaging (MRI) showed a middle/posterior mediastinal mass anterior to the esophagus and adherent to the left atrium (Figure 1). Post-transplant lymphoproliferative disorder was suspected, and the patient underwent bronchoscopy with mediastinal lymph node biopsy; the sample had unrevealing cytology and negative cultures. Thereafter, video assisted thoracoscopic surgery was used to obtain a biopsy sample of the lesion. The sample revealed multifocal necrotizing granulomatous inflammation with 1991
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suggestive of an infarct. Further imaging with echocardiography and cardiac MRI defined a 4-cm-diameter lobulated filling defect contiguous with the posterior wall of the left atrium, without involvement of the mitral valve. Surgical excision was undertaken and invasive aspergillosis was confirmed pathologically and by growth of the organism in culture. Multiple complications developed after the operation, including recurrent atrial tachyarrhythmias, bacterial sepsis, acute renal failure, embolic stroke, and ultimately, death after a prolonged hospital course.
Figure 1. Magnetic resonance image demonstrates a well-defined middle mediastinal mass adjacent to the left atrium (LA). IVC, inferior vena cava, Ao, aorta.
invasive fungal hyphal elements (Figure 2) and the drainage grew Aspergillus fumigatus. Treatment was initiated with IV amphotericin B lipid complex. However, this was associated with subsequent elevation of creatinine by Day 3 of treatment. Acute renal failure progressed despite a change to liposomal amphotericin B. Therapy was switched to IV caspofungin and voriconazole. Subsequently, acute respiratory failure developed due to acute rejection and cytomegalovirus pneumonitis. Because of persistent high-grade fevers, she underwent thoracoscopy and excision of the mass several days after the first surgery. Pathologic examination revealed dense fibrous tissue with multifocal necrotizing granulomatous inflammation. Numerous septated fungal hyphae with acute angle branching were identified with Gomori methenamine silver stain. Cultures grew Aspergillus fumigatus. The patient tolerated surgery well. Her renal failure resolved and fevers remitted. Post-operative MRI showed no evidence of residual mass. She was treated with a combination of oral voriconazole (200 mg twice a day) and IV caspofungin (50 mg daily) for 9 additional weeks, and then continued long-term on the same dose of voriconazole without clinical symptoms or radiographic recurrence on serial CT scans. At 16 months follow-up, in the absence of clinical signs of recurrent disease, a serial follow-up chest CT scan revealed a low-density filling defect measuring at least 3 ⫻ 2 cm in the left atrium that was suspicious for a thrombus or mass and a low-density splenic lesion
DISCUSSION To our knowledge, this is the first reported case of a mediastinal mass caused by an Aspergillus species in a solid organ transplant recipient. Mediastinal involvement with Aspergillus species has been reported rarely. A fatal case of A. flavus fibrosing mediastinitis was described in a non-immunocompromised farmer in 1981.5 In addition, posterior mediastinal invasion by A. fumigatus was reported in 3 pediatric patients with acute leukemia: 2 had ruptured aortic aneurysms and 1 had a paravertebral abscess.6 Aspergillus is a ubiquitous mold found worldwide that reproduces by conidia and spreads via air transmission. A fumigatus is the most common cause of infections, followed by A niger and A flavus. Aspergillus can colonize lung tissue without causing disease or can cause invasive disease of bronchi (tracheobronchitis) and lung parenchyma (pneumonitis). Aspergillus colonization is diagnosed when a culture of BAL fluid grows Aspergillus in the absence of tracheobronchitis or pneumonia. Tracheobronchitis or anastomotic infections are characterized by inflammation and/or ulceration of the respiratory mucosa with typical hyphae
Figure 2. Gomori methenamine silver stain of surgical biopsy specimen demonstrates the presence of fungal elements.
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detected from biopsy samples of abnormal tissue. A definitive diagnosis of invasive parenchymal disease requires the demonstration of hyphae in lung tissue that grows Aspergillus.7,8 Invasive infections are reported to occur in 1% to 15% of solid organ transplant patients, with highest incidence in heart-lung or lung transplant patients.2,9 Because of the vascular tropism of the Aspergillus species, virtually any organ can be involved, but the lungs are the site of infection in an overwhelming majority of the cases.2,3 Both colonization and invasive disease are most common in the first year after transplantation, although they may occur later.4 In a review by Guillemain et al,2 mortality from invasive disease was reported to be 73%, with a range of 30% to 75% in other studies. Most deaths occurred in recipients with pneumonia or disseminated disease. Single-lung transplant recipients with Aspergillus infections are reported to have a higher mortality rate, and this may be related to a higher incidence of pneumonia rather than tracheobronchial infections.10 Postulated risk factors for invasive Aspergillus infection after lung transplantation include a pre-transplant diagnosis of cystic fibrosis, pre- and post-transplantation colonization with Aspergillus species, and post-transplant CMV infections.11–13 Several studies have demonstrated that cystic fibrosis patients colonized with Aspergillus before transplantation do not have a higher incidence of pulmonary or disseminated disease after transplantation. However, they are at increased risk of anastomotic infections in the early post-transplantation period.11–14 Aspergillus colonization before transplantation has been associated with the development of invasive infection. Studies report that 3% to 20% of patients with colonization before transplantation progress to invasive disease.12,15,16 In one study, lung transplant recipients colonized with Aspergillus in the first 6 months after transplantation were 11 times more likely to develop invasive disease than were non-colonized patients.16 Other factors such as acute graft failure or rejection, bronchial ischemia, and anastomotic dehiscence have been proposed to place lung transplant recipients at increased risk of invasive fungal infection.10 CMV disease is another risk factor associated with invasive Aspergillus infection in lung transplant recipients. In Guillemain’s study,2 29% of all organ transplant patients with invasive Aspergillus infection had concurrent CMV disease. In the lung transplant population, 57% to 86% of patients with invasive Aspergillus infection have concurrent CMV disease.15,17 Our patient was CMV D⫹/R⫺ and developed severe CMV pneumonitis subsequent to the diagnosis of invasive aspergillosis. It is not clear from currently available data whether lung transplant recipients should receive routine pro-
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phylaxis against Aspergillus or only after pulmonary colonization has been detected. Prophylaxis has been recommended for lung transplant recipients at high risk of an invasive fungal infection.18 Controlled trials are lacking regarding the choice, mode of administration, and duration of anti-fungal agents for prophylaxis in such lung transplant recipients. Current data and practice are derived from small case series, uncontrolled trials, and limited prospective non-comparative studies that suggest the utility of inhaled amphotericin with or without oral itraconazole.4,16,19 Newer azoles, such as voriconazole, may have improved efficacy but have not been studied as prophylaxis in lung transplant recipients. A prompt and aggressive work-up and initiation of therapy is indicated upon suspicion of an invasive Aspergillus infection in lung transplant patients, especially in the context of positive respiratory cultures.7 Intravenous therapy with maximally tolerated doses of amphotericin B followed by prolonged itraconazole was the traditionally recommended therapy.7 However, voriconazole, an extended spectrum highly lipophilic triazole with 98% oral bioavailability, was recently found to be superior to conventional IV amphotericin B in a multicenter, randomized, open-label trial for initial therapy of invasive aspergillosis in patients, most of whom had hematologic cancers and neutropenia.20 The results of this study have led to the use of voriconazole as primary therapy to treat invasive aspergillosis in lung transplant recipients. However, treatment trials with voriconazole in this patient population are needed. Other potentially effective therapies include lipid formulation of amphotericin and echinocandins such as caspofungin. Acute renal failure developed in our patient during her initial treatment with amphotericin B lipid complex. After the surgical resection, a combination of voriconazole and caspofungin was used. Caspofungin has been approved for salvage therapy of invasive aspergillosis21 and has been shown recently to have equal efficacy with less toxicity compared with liposomal amphotericin in patients with fever and neutropenia.22 A combination of voriconazole and caspofungin has been tested in vitro against 48 different clinical isolates of Aspergillus species. Most of the interactions (87.5%) were synergistic in nature, with no antagonism observed. Although the mechanism of the interactive effect is unknown, simultaneous disruption of fungal cell membrane by voriconazole and the cell wall by caspofungin has been proposed.23 Combination therapy using a triazole and an echinocandin, and evaluated in an animal model, led to a significant reduction in mortality, pulmonary infiltrates, and fungal burden in neutropenic rabbits with invasive pulmonary aspergillosis.24 In our patient, combination
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therapy initially led to a complete clinical and radiographic response. Unfortunately, fatal relapse occurred after 1 year, despite long-term maintenance therapy with voriconazole. In conclusion, this rare case highlights the potential of Aspergillus to cause a broad variety of clinical presentations, including mediastinal and cardiac masses. It also demonstrates that invasive disease can occur despite prophylaxis and is not necessarily preceded by colonization on surveillance bronchoscopies. Despite the availability of new anti-fungal agents, invasive aspergillosis remains an important life-threatening complication of lung transplantation. REFERENCES 1. Chaparro C, Maurer JR, Chamberlain D, et al. Causes of death in lung transplant recipients. J Heart Lung Transplant 1994;13:758 – 63. 2. Guillemain R, Lavarde V, Amrein C, Chevalier P, Guinvarc’h A, Glotz D. Invasive aspergillosis after transplantation. Transplant Proc 1995;27:1307–9. 3. Mehrad B, Paciocco G, Martinez FJ, Ojo TC, Iannettoni MD, Lynch JP 3rd. Spectrum of Aspergillus infection in lung transplant recipients. Chest 2001;119:169 –75. 4. Minari A, Husni R, Avery RK, et al. The incidence of invasive aspergillosis among solid organ transplant recipients and implications for prophylaxis in lung transplants. Transpl Infect Dis 2002;4:195–200. 5. Ahmad M, Weinstein AJ, Hughes JA, Cosgrove DE. Granulomatous mediastinitis due to Aspergillus flavus in a nonimmunosuppressed patient. Am J Med 1981;70:887–90. 6. Wells WJ, Fox AH, Theodore PR, Ross LA, Stanley P, Starnes VA. Aspergillosis of the posterior mediastinum. Ann Thor Surg 1994;57:1240 –3. 7. Stevens DA, Kan VL, Judson MA, et al. Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America. Clin Infect Dis 2000;30:696 –709. 8. Kramer MR, Denning DW, Marshall SE, et al. Ulcerative tracheobronchitis after lung transplantation: A new form of invasive aspergillosis. Am Rev Resp Dis 1991;144: 552– 6. 9. Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev 2005;18:44 – 69. 10. Singh N, Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management. J Heart Lung Transplant 2003;22:258 – 66.
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11. Paradowski LJ. Saprophytic fungal infections and lung transplant—revisited. J Heart Lung Transplant 1997;16: 524 –31. 12. Nunley DR, Ohori P, Grgurich WF, et al. Pulmonary aspergillosis in cystic fibrosis lung transplant recipients. Chest 1998;114:1321–9. 13. Flume PA, Egan TM, Paradowski LJ, Detterbeck FC, Thompson JT, Yankaskas JR. Infectious complications of lung transplantation: impact of cystic fibrosis. Am J Resp Crit Care Med 1994;149:1601–7. 14. Helmi M, Love RB, Welter D, Cornwell RD, Meyer KC. Aspergillus infection in lung transplant recipients with cystic fibrosis: risk factors and outcomes comparison to other types of transplant recipients. Chest 2003;123:800 – 8. 15. Yeldandi V, Laghi F, McCabe MA, et al. Aspergillus and lung transplantation. J Heart Lung Transplant 1995;14: 883–90. 16. Cahill BC, Hibbs JR, Savik K, et al. Aspergillus Airway colonization and invasive disease after lung transplantation. Chest 1997;112:1160 – 4. 17. Husni RN, Gordon SM, Longworth DL, et al. Cytomegalovirus infections is a risk factor for invasive aspergillosis in lung transplant recipients. Clin Infect Dis 1998;26:753–5. 18. Green M, Avery RK, Preiksaitis J (editors). Guidelines for the prevention and management of infectious complications of solid organ transplantation. Am J Transplant 2004;4(suppl 10):110 –34. 19. Reichenspurner H, Gamberg P, Nitschke M, et al. Significant reduction in the number of fungal infections after lung- heart-lung, and heart transplantation using aerosolized amphotericin B prophylaxis. Transplant Proc 1997; 29:627– 8. 20. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole vs. amphotericin B for primary therapy of IA. N Engl J Med 2002;347:408 –1. 21. Johnson MD, Perfect JR. Caspofungin: first approved agent in a new class of antifungals. Expert Opin Pharmacother 2003;4:807–23. 22. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004;351:1391– 402. 23. Perea S, Gonzalez G, Fothergill AW, Kirkpatrick WR, Rinaldi MG, Patterson TF. In vitro interaction of caspofungin acetate with voriconazole against clinical isolates of Aspergillus spp. Antimicrob Agents Chemother 2002;46:3039 – 41. 24. Petraitis V, Petraitiene R, Sarafandi AA, et al. Combination therapy in treatment of experimental pulmonary aspergillosis: synergistic interaction between an antifungal and an echinocandin. J Infect Dis 2003;187:1834 – 43.
