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Ann Thorac Surg 2006;82:338-340
© 2006 The Society of Thoracic Surgeons

Case report

Treatment of Cavitary Pulmonary Zygomycosis With Surgical Resection and Posaconazole

Subroto Paul, MD a , Francisco M. Marty, MD b , Yolonda L. Colson, MD, PhD a , *

a Division of Thoracic Surgery, Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts
b Department of Surgery and Division of Infectious Disease, Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts

Accepted for publication September 1, 2005.

* Address correspondence to Dr Colson, Brigham and Women's Hospital, Division of Thoracic Surgery, 75 Francis St, Boston, MA 02115 (Email: ycolson{at}partners.org).


   Abstract
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 Abstract
Introduction
 Comment
 References
 
We describe a 57-year-old woman with acute lymphoblastic leukemia who had a cavitary lesion develop in the right upper lobe caused by Cunninghamella bertholletiae, a zygomycete. The infection was resistant to both high-dose liposomal amphotericin B and voriconazole. The current report demonstrates successful treatment, even in the setting of subsequent bone marrow transplantation and immunosuppression, using a combination of surgical resection and posaconazole therapy.


   Introduction
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Acute lymphocytic leukemia (ALL) is a progressive malignant disease that is characterized by the presence of large numbers of immature white blood cells that resemble lymphoblasts found throughout the bone marrow and other organs. Bone marrow transplantation offers a potenital cure for patients afflicted with ALL. However the resulting immunosupression can often lead to devasting infectious complications.

An otherwise healthy 57-year-old woman presented with a 2-week to 3-week history of a persistent upper respiratory infection and was found to be pancytopenic with circulating blasts. The patient was subsequently diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and underwent induction chemotherapy with daunorubicin, vincristine, L-asparaginase, and prednisone.

The patient initially did well but was readmitted to the hospital a month later experiencing increasing fatigue and chills for 5 days. The patient was found to have significant hepatic dysfunction attributed to L-asparaginase and confounded by the concomitant use of imatinib, which had been started after induction chemotherapy. The patient was febrile to 38.0°C and neutropenic (300 leukocytes/µL), and hence she was started empirically on vancomycin, cefepime, and liposomal amphotericin B (5 mg/kg/day). An admission chest roentgenogram demonstrated a right upper lobe (RUL) consolidation. A chest computed tomographic scan confirmed an RUL pleural-based mass consolidation as well as several other small pulmonary nodules, mostly in the left lower lobe. The patient underwent a fine-needle aspiration of the RUL lesion and was found to have broad nonseptate fungal forms consistent with zygomycetes infection. Vancomycin and cefepine were discontinued after her neutropenia resolved, and she was maintained on liposomal amphotericin B. A follow-up chest computed tomographic scan done 1 week later demonstrated an increase in the size of the lesion with new cavitation (Fig 1). A short course of voriconazole resulted in further clinical progression of the RUL mass, such that liposomal amphotericin B was resumed at a higher dose (7.5 mg/kg/day). The patient was maintained on imatinib during this time for Ph+ ALL therapy.


Figure 1
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  		Fig 1. (a) Preoperative chest roentgenogram illustrating cavitary lesion in the right upper lobe (arrow). (b) Preoperative chest computed tomographic scan illustrating the cavitary lesion in the right upper lobe with the contained fungus ball (arrow).

 
Her clinical course continued to deteriorate, and she was subsequently referred for further treatment of this progressive infection and for evaluation as a potential candidate for allogeneic bone marrow transplantation as definitive treatment of Ph+ ALL. The patient consented to receive posaconazole, an investigational azole active against zygomycetes. However the RUL mass had increased in size; now given its large size and degree of pulmonary parencyhmal necrosis and cavitation, effective treatment was not possible with antifungal therapy alone. The patient underwent a right upper lobe apical segmentectomy with a partial pleurectomy through a right thoracotomy for complete resection of this large fungal mass. The bronchial stump was covered, and the postresection pleural space was filled with a latissimus dorsi muscle flap to decrease the risk of breakdown of the airway staple line secondary to infection with the subsequent development of a brochopleural fistula or a fungal empyema. Resected lung tissue grew Cunninghamella bertholletiae.

The patient rapidly recovered and was maintained on posaconazole and imatinib throughout her course. She was subsequently evaluated as a bone marrow transplant candidate and when a 5/6 HLA antigen match donor became available, the patient underwent a successful myeloablative allogeneic hematopoietic stem cell transplant 4 months after surgical resection of the RUL fungal mass. She was conditioned for hematopoietic stem cell transplant with cyclophosphamide and total body irradiation. The patient received both tacrolimus and sirolimus for graft versus host disease prophylaxis. A chest computed tomographic scan before transplantation showed no signs of recurrent fungal infection in the RUL, and the latissimus dorsi muscle flap filled the residual apical space adjacent to the area of resection (see arrows; Fig 2). Her initial posttransplant course was remarkable for neutropenic colitis, which eventually resolved. She was subsequently discharged home on an immunosuppressive regimen of tacrolimus and sirolimus. She was maintained on posaconazole throughout her course with no evidence of recurrent fungal infection despite her immunosuppressed state.


Figure 2
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  		Fig 2. (a) Postoperative chest roentgenogram illustrating latissimus dorsi muscle flap obliterating residual space in right apex of the chest (arrow). (b) Postoperative chest computed tomographic scan illustrating latissimus dorsi muscle flap filling the pleural space in the right apex (top) and extending into the fissure to cover the bronchial stump after apical segmentectomy (bottom) (arrow).

 

   Comment
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 Abstract
 Introduction
 Comment
References
 
Cunninghamella bertholletiae infection is a rare cause of pulmonary zygomycosis. It is typically isolated in pulmonary bronchial isolates only as a contaminant [1]. However, in immunosuppressed hosts such as those with hematologic malignancies or those actively immunosuppressed after transplantation, invasive infection can take hold [1, 2]. We describe a 57-year-old woman with ALL who developed a RUL cavitary lesion caused by Cunninghamella bertholletiae, which progressed despite treatment with high-dose liposomal amphotericin B (7.5 mg/kg/day). Voriconazole was administered briefly, but it is not as active against zygomycetes [3, 4]. The patient's infection resolved clinically with resection of the cavitary lesion and long-term posaconazole therapy. There was no evidence of relapse of her infection despite myeloablative conditioning for hematopoietic stem cell transplant. The presence of zygomycosis in immunocompromised hosts is rare, but it has been increasingly reported and is associated with a 50% to 70% mortality [2, 3, 5]. Although there are isolated case reports of effectively treating zygomycosis with amphotericin B and resection, most attempts at treating zygomycosis with other antifungal agents (with or without surgical resection) have noted recurrent zygomycosis after bone marrow transplantation [2, 3, 5–7].

This report represents the second reported successful use of posaconazole in the treatment of zygomycosis in an immunocomprised host. The previous report described the case of a diabetic patient who after heart and kidney transplantation had invasive Rhizopus infection develop that was resistant to amphotericin B therapy but improved with posaconazole alone. No resection was required as the patient had a diffuse mediastinal and pleural-based infection [5]. Therefore, the current article represents the first reported use of posaconazole therapy with surgical resection in the treatment of pulmonary zygomycosis. This approach resulted in both the excision of the large necrotic cavitary mass within the lung to minimize the amount of fungus present, but also prevented the recurrence of zygomycosis in the immunocompromised state after bone marrow transplantation.

Posaconazole is a new potent, extended-spectrum, triazole antifungal agent that is highly active against a wide array of yeasts and molds, including Aspergillus, Fusarium and Zygomycetes, which are often refractory to other antifungals [8]. It is currently under investigational use. Posaconazole is different from current generation triazoles in that it is not extensively metabolized by thecytochrome P450 (CYP) enzymes and is a fairly specific CYP3A4 inhibitor [8].

Our case is the first to demonstrate the combined utility of surgery along with posaconazole therapy in the setting of hematologic malignancy and subsequent bone marrow transplantation. It is also the first published account of successful bone marrow transplantation after surgical treatment for pulmonary zygomycosis. This case illustrates the utility of perioperative posaconazole as an effective agent against zygomycetes and the importance of removing necrotic infected tissue in the treatment of extensive zygomycotic pulmonary infection [1], as this subsequently permitted the patient to safely undergo myeloablative hematopoietic stem cell transplant. Resection of lung parenchyma not involved does not have added benefit and thus segmentectomy is sufficient for this care. Finally, two technical points are highlighted: (1) the importance of muscle flap coverage of the bronchial stump for the prevention of airway dehiscence and bronchopleural fistulas, and (2) obliteration of the residual pleural space present after lung resection to prevent the formation of a fungal empyema or cavity [9]. Partial surgical resection or contamination of the pleural space during surgical resection can take a potentially treatable, localized site of infection and make it no longer resectable, or worse, prevent patients from undergoing the life-saving hematopoietic stem cell transplant they require for treatment of their hematologic malignancy.

Zygomycosis is a serious infection in immunocompromised hosts, which leads to significant mortality in this population. The current report demonstrates that aggressive therapy with combination of surgical resection and posaconazole therapy can result in the successful long-term treatment of pulmonary zygomycytes despite resistance to traditional antifungal therapy.


   References
Top
 Abstract
 Introduction
 Comment
 References
 

  1. Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease Clin Microbiol Rev 2000;13(2):236-301.[Abstract/Free Full Text]
  2. Rickerts V, Bohme A, Viertel A, et al. Cluster of pulmonary infections caused by Cunninghamella bertholletiae in immunocompromised patients Clin Infect Dis 2000;31(4):910-913.[Abstract/Free Full Text]
  3. Marty FM, Cosimi LA, Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants N Engl J Med 2004;350(9):950-952.[Medline]
  4. Chen A, Sobel JD. Emerging azole antifungals Expert Opin Emerg Drugs 2005;10(1):21-33.[Medline]
  5. Tobon AM, Arango M, Fernandez D, Restrepo A. Mucormycosis (zygomycosis) in a heart-kidney transplant recipientrecovery after posaconazole therapy. Clin Infect Dis 2003;36(11):1488-1491.[Medline]
  6. Pavie J, Lafaurie M, Lacroix C, et al. Successful treatment of pulmonary mucormycosis in an allogenic bone-marrow transplant recipient with combined medical and surgical therapy Scand J Infect Dis 2004;36(10):767-769.[Medline]
  7. Leleu X, Sendid B, Fruit J, et al. Combined anti-fungal therapy and surgical resection as treatment of pulmonary zygomycosis in allogeneic bone marrow transplantation Bone Marrow Transplant 1999;24(4):417-420.[Medline]
  8. Kale P, Johnson LB. Second-generation azole antifungal agents Drugs Today (Barc) 2005;41(2):91-105.
  9. Colwell AS, Mentzer SJ, Vargas SO, Orgill DP. The role of muscle flaps in pulmonary aspergillosis Plast Reconstr Surg 2003;111(3):1147-1150.[Medline]



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